NZ577150A

NZ577150A - Imidazopyridine inhibitors of iap

Info

Publication number: NZ577150A
Application number: NZ577150A
Authority: NZ
Inventors: Michael F Koehler
Original assignee: Genentech Inc
Priority date: 2006-12-19
Filing date: 2007-12-14
Publication date: 2012-04-27
Also published as: WO2008079735A1; AU2007337104A1; US20120015974A1; BRPI0719481A2; RU2009127800A; CN101605786A; US20100130539A1; US8063218B2; IL198927A0; JP2010513561A; KR20090094461A; RU2466131C2; CA2671607A1; EP2125809A1

Abstract

Disclosed are 2-(imidazo[1,2-a]pyridin-2-yl)pyrrolidine derivatives as represented by the general formula (I), wherein: X1 and X2 are each independently O or S; Y is CH2; Z is H, alkyl, a carbocycle or a heterocycle which may be substituted; Q is H, halogen, hydroxyl, carboxyl, amino, nitro, cyano, alkyl, a carbocycle or a heterocycle; wherein said alkyl, carbocycle and heterocycle may be substituted; R1, R3', R4', R5, R6 and R6' are each hydrogen; R2 is morpholino or cyclohexyl; R3 and R4 are methyl; R7 is H, cyano, hydroxyl, mercapto, halogen, nitro, carboxyl, amidino, guanidino, alkyl, a carbocycle, a heterocycle or -U-V; R8 is H, alkyl, a carbocycle or a heterocycle wherein one or more CH2 or CH groups of said alkyl is optionally replaced with -O-, -S-, -S(O)-, S(O)2, or -C(O)-; and said alkyl, carbocycle and heterocycle is optionally substituted; and m is 0 to 4; or a salt or stereoisomer thereof. Representative compounds include those where the 2-(imidazo[1,2-a]pyridin-2-yl)pyrrolidine moiety is substituted on the 1-position with N-methyl-L-alanine-L-cyclohexylglycine or N-methyl-L-alanine-L-morpholin-4-ylglycine. Further disclosed is a pharmaceutical composition which comprises a compound as defined above and a carrier, diluent or excipient for the treatment of cancer.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 577150 Received at IPONZ on 2 March 2012 LMIDAZOPYRIDINE INHIBITORS OF IAP CROSS-REFERENCE TO RELATED APPLICATIONS 5 Tliis application claims priority under 35 U.S.C. § 119(e) to U.S.S.N, 60/870,821, filed December 19, 2006, which is incorporated by reference in its entirety. The reader's attention is also directed to our related divisional New Zealand Patent Specification No. 591446, 10 The present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of IAP proteins useful for treating cancers. 15 Apoptosis or programmed eel death is a genetically and biochemically regulated mechanism that plays an important role in development and homeostasis in invertebrates as well as vertebrates. 20 Aberrancies in apoptosis that lead to premature cell death have been linked to a variety of developmental disorders. Deficiencies in apoptosis that result in the lack of cell death have been linked to cancer and chronic viral infections (Thompson et al, (1995) Science 267, 1456-1462). One of the key effector molecules in apoptosis are the caspases {cysteine containing aspartate 25 specific proteases). Caspases are strong proteases, cleaving after aspartic acid residues and once activated, digest vital eel proteins from within the cell. Since caspases are such strong proteases, tight control of this family of proteins is necessary to prevent premature cell death. In general, caspases are synthesized as largely inactive zymogens that require proteolytic processing in order to be active. This proteolytic processing is only one of the ways in which caspases are regulated. The 30 second mechanism is through a family of proteins that bind and inhibit caspases. A family of molecules that inhibit caspases are the Inhibitors of Apoptosis (IAP) (Deveraux et al, J Clin Immunol (1999), 19:338-398). IAPs were originally discovered in baeulovirus by their functional ability to substitute for P35 protein, an anti-apoptotic gene (Crook et al. (1993) J 35 Virology 67, 2168-2174). IAPs have been described in organisms ranging from Drosophila to 1 WO 2008/07^735 PCT/US2007/087532 human. Regardless of their origin, structurally, IAPs comprise one to three Baculovirus IAP repeat (Bill) domains, and most of them also possess a carboxyl-termtrial RING finger motif. The B1R domain itself is a zinc binding domain of about 70 residues comprising 4 alpha-helices and 3 beta strands, with cysteine and bistidine residues that coordinate the zinc ion (Hinds et al., (1999) 5 Nat. Struct. Biol. 6. 648-651), It is the B1R domain that is believed to cause the anti-apoptotic effect by inhibiting the caspases and thus inhibiting apoptosis. As an example, human X-chrotnosome linked IAP (X1AP) inhibits caspase 3, caspase 7 and the Apaf-1 -cytochrome C mediated activation of caspase 9 (Deveraux et al., (1998) EM BO J. 17, 2215-2223), Caspases 3 and 7 are inhibited by the BIR2 domain of XIAP, while the BIR3 domain of XIAP is responsible 10 for the inhibition of caspase 9 activity. XIAP is expressed ubiquitously in most adult and fetal tissues (Liston et al, Nature, 1996, 379(6563);349), and is overexpressed in a number of tumor cell lines of the NCI 60 cell line panel (Fong et al, Genomics, 2000, 70:113; Tamm et al, Clin. Cancer Res. 2000, 6(5): 1796). Overexpression of XIAP m tumor cells has been demonstrated to confer protection against a variety of pro-apoptotic stimuli and promotes resistance to 15 chemotherapy (LaCasse et al. Oncogene, 1998, I7(25):3247). Consistent with this, a strong correlation between XIAP protein levels and survival has been demonstrated for patients with acuie myelogenous leukemia (Tamm et at, supra), Down-regulation of XIAP expression by antisense oligonucleotides has been shown to sensitize tumor cells to death induced by a wide range of pro-apoptotic agents, both m vitro and in vivo (Sasaki el al, Cancer Res., 2000, 20 60(20):5659; Lin et ai. Biochem J.. 2001, 353:299; f-Iu et al, Clin. Cancer Res., 2003, 9(7):2826). Smac/DIABLG-derived peptides have also been demonstrated to sensitize a number of different tumor cell lines to apoptosis induced by a variety of pro-apoptotic drugs (Arnt et al, J. Biol, Chem., 2002, 277(46):44236; Futda et al, Nature Med., 2002, 8(8):808; Guo et al, Blood,2002, 99(9):341.9; Vucic et al, j, Biol. Chem.,2002, 277(14): 12275; Yang et al, Cancer Res,, 2003, 25 63(4):831). Melanoma IAP (ML-IAP) is an IAP not detectable in most normal adult, tissues but is strongly upregulated in melanoma (Vucic et al., (2000) Current Bio 10:1359-1366). Determination of protein structure demonstrated significant homology of the ML-IAP B1R and RING finger 30 domains to corresponding domains present in human XIAP, C-IAPi and C-IAP2. The B1R domain of Ml,-IAP appears to have the most similarities to the B1R2 and BIR3 of XIAP, C-1AP1 and C-IAP2, and appears to be responsible for the inhibition of apoptosis, as determined by deletional analysis. Furthermore, Vucic et al,, demonstrated that ML-IAP could inhibit chemotherapeutic agent induced apoptosis. Agents such as adriamycin and 4-tertiary butyiphenol 35 (4-TBP) were tested in a cell culture system of melanomas ovcrexpressing ML-IAP and the , chemotherapeutic agents were significantly less effective in killing the cells when compared to a 2 Received at IPONZ on 2 March 2012 normal melanocyte control. The mechanism by which ML-IAP produces an anti apoptotic activity is in part through inhibition of caspase 3 and 9. ML-IAP did not effectively inhibit caspases 1, 2, 6, or 8, Since apoptosis is a strictly controlled pathway with multiple interacting factors, the discovery that IAPs 5 themselves are regulated was not unusual. In the fruit fly Drosophila, the Reaper (rpr), Head Involution Defective (hid) and GRIM proteins physically interact with and inhibit the anti-apoptotic activity of the Drosophila family of IAPs. In the mammal, the proteins SM AC/DIABLO act to block the IAPs and allow apoptosis to proceed. It was shown that during normal apoptosis, SMAC is processed into an active form and is released from the mitochondria into the cytoplasm where it physically binds to IAPs and prevents 10 the IAP from binding to a caspase. This inhibition of the IAP allows the caspase to remain active and thus proceed with apoptosis. Interestingly, sequence homology between the IAP inhibitors shows that there is a four amino acid motif in the N-terminus of the processed, active proteins. This tetrapeptide appears to hind into a hydrophobic pocket in the MR domain and disrupts the BIR domain binding to caspases (Chai et al., (2000) Nature 406:855-862, Liu et al., (2000) Nature 408:1004-1008, Wu et al„ (2.000) Nature 408 15 1008-1012). In the description in this specification reference maybe made to subject matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this 20 application. SUMMARY OF THE INVENTION In one aspect of the present invention there is provided a compound of formula (1): wherein Xj and Xi are each independently O or S; Y is CH2; Z is II, alkyl, a carbocycle or a beterocycle; wherein said alkyl, carbocyele and heterocycle is 30 optionally substituted with one or more hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, 3 Received at IPONZ on 2 March 2012 optional!}' substituted aik\i, amino, cyano. nitro, amidino. guanidino. r.n optionh 1 ly substituted earbueyde 01 an optionally suInstituted heierocycie, and wherein one or more Cl I. or I'll groups olan alkyl is optionally replaced with -S-. -StOk S(0)7. -N(R>;)-. -CfO)-. -C(0>-NR,;-, -NRs-('(O)-. ~SOrNRr, -NRrSD-. -NK.>-C(0)-NRs-, -NR;,-C(N'il)-NR,-, -NR-<-( '(NH)-. -C(0)-r>. or -0-C(0K 5 (.} is II, halogen hydroxyl, earbo.xyl ammo. nitro. evano. alkyl. a earboeycle or a hueroeycle; wherein s.ii.j .ilkyl, carbocuie and heteroeyele is optionally substituted with one or more hydroxyl, alkoxy, acyl. halogen. mercupf<>. o\o. eurbo.xy 1, ;icyi. optionally substituted alkyl. amino,, cyano, nitro.. amidino. guanidino. an optionally substituted carlsocyele or an optionally substituted heteroeyele; and wherein one or more CI I. or < '1 i groups of an alkyl is optionally replaced with -O-. -S-, -S( (.))•, S(OK -N(R<i)-, -('(())•„ 10 -( (OJ-NR.,-. -NR,-UOl -S< K-NRj,-, -NRx-SO. . NKr(.'(< ))-NI'V. -NlVQNl IfNlV. -NIVUNU)-. -('((.))-<)- or -()-("<Ok R; is H: R. K tisorpholmo or cyclohexyi; Rj is metbvL 15 R„" is H: K.: is methyl; R.f is j-J; R, is II. R,:, -and R-.' are each H. 20 R- is li, cyano. hydroxyl. mercapto. halogen, nitro. cas'boxy). amidino, guanidino, alkvl, a earbocvele, a he:eroe\c!e or wherein U is -5-, -S(O)-, S(0)j. -N(Rk)-. -C(O)-. -CfOJ-NRx-, -NR,,-OOK ->OrNR<.-; -NRt,-SOr. -NRs-C(0)-NR,,-. -NRS-C(NH)-N;1V, -NRs-C(NII)-, -C(O)-C)- or -O-CtO)- and V is alkyl a carbocycle or a heteroeyele, and wherein one or more CHi or CH groups of on alkvl je optionally replaces! with -0-. -S-. -5(0)-. S(O),., -N(RS.K -C(O)-, -C(0)-NRs-. -NRrC(0)-, -SO:r 25 NR.;-. -NRi-SO:-. -NRi-C(0.»-NR.«-. -C(0)-0- or -O-CfO)-; and an alkyl carbocycle and heteroeyele is optionally substituted with hydroxyl alkoxy. acyl halogen, mercapto. oxo, carboxyj. acyl halo-substituted alkyl. amino, cyano nitro. amidino. guanidino. an optional ly substituted carbocycle or an optionally substituted heteroeyele: R>. is H. alkyl a carbocycle or a heteroeyele wherein one or more CH,< or CH groups of said alkyl 30 is optionally replaced with -O-, -S-, -S(O')-, S(0'K or -C(O)-; and said alkyl. carbocycle and heteroeyele is optionally substituted vmli hydroxyl. alkoxy, acyl halogen, mercapto, oxo (=0), earboxyl, acyl, halo-snbsjirured alkvl. amino, cyano nitro, amidino. guanidmo, an optionally substituted carbocycle or an optionally substituted heteroeyele; and in is 0 to 4: 35 wherein, for each occurrence, alkyl is independently a branched or nnbranched, saturated or unsaturated aliphatic hydrocarbon; 4 Received at IPONZ on 2 March 2012 of a salt in* siercoisaaua' thereof I he compounds of formula (I) arc inhibitors of JAP. In unnshcr aspect o! she invention. ilicrc arc provided compositions comprising compounds of formula 1 5 and a carrier, diluent or excipieiH. hi smother aspeci described is a method of inducing apoptosis in a cell comprising introducing inlo said cell a compound of foi inula I. 10 In another a spec i described is a method of sensitizing a cell to an apopiolie signal comprising introducing into said cell ,i compound of formula I. hi another aspect described is a method for inhibiting the binding of .in IAP protein to a caspase protein comprising cuiituctuig said i.\F protein with a compound of formula 1. 15 In another aspect desenbed is a method for treating a disease or condition associated with the uvcrc-xpiessnm s>i an IAP proieas in a mammal, compnsmg administering to said mammal an effective amount ol'.i compound of formula I» 20 1 he i mention also relates to use of a compound of the invention in the manufacture of a medicament for the treat men i of the human or animal body The invention also relates to use of a compound of the invention in the manufacture of a medicament for the treatment ot a disease or condition associated with the overexpression of an IAP in a mammal. 25 The invention also relates to use of a compound of die invention in the manufacture of a medicament for the treatment of canccr. The invention also presides a compound of the invention for use in a mefhod of treatment of the human or 30 animal body. The invention also provides a compound of the invention for use in a method of treatment of a disease or condition associated with (be oierexpression of an IAP m a mammal. 35 The invention also provides a compound of the invention for use in a method of treatment of cancer. The invention also relates to use of a compound of the invention in combination with a compound selected from the group consisting of cytarabine. iludarabine. 5-fluoro-2"-dcoxyuiridine, gemeitabme, methotrexate, bleomycin, cispiatin, cyclophosphamide, adriamycin (doxorubicin), rn i tox an trone, 5 (followed by page 5a) Received at IPONZ on 2 March 2012 cnmptotheesn. Eopoteciin. coicemsd. colchicine, paclitaxel. vinblastine, vincristine, tamoxifen. Finasteride, ta.xotcrc and mitomycin (.' or nuiuilion in the manuiacture of a mcdicanietit fur the treatment of cancer. The unensio!) also rehnes to a compound of the invention in combination with a compound selected from 5 the group eunxisuiu:: of eyiarabine, fhulaiabtne. .M1uoro--2"--deoxytiiridme. ir.ctiieitnbme, met hot res ate. bleoimctn. cKphiUfi. cyclophosphamide, adriauiycni (doxorubicin). niitoxantione, cariiptotlitxnt, topoiecan. coleemid. colchicine. paclitaxel, vinblastine, vinei istine. tamoxifen, finasteride. taxotere and miU'-niycin C. os radiation ior use in die treatment of cancer l>! f AiLIilJ DhSCRlPnON OF filh PRI'FHRRhF) liMBODlMiiNTS 10 'i'he teim "comprising'' as used in this .specification means "consisting ai least m part of". When interpreting each statement in this specification thai includes the term "comprising", lea lines oilier than that or those prefaced by ihe term may also be present Related terms such as "comprise" and "comprises" me to he inteif-seted in '.he same manner. l.> "Acyi" means a carbonyl containing sabsiiinent represented by the formula -C(0)-R in which R is II, atkyh a earboeyde, n heteroeyele. carbocycle-substiUited alkyl or heterocycle-snbstituted alkvl wlieretn the alkyl. alkoxy. carboe>c!e and heteroeyele are as defmerf herein Acyl groups include alkanoyl (e.g. acetyl), aroyl Se.g. benzoyl), and heterearoyl. 20 •'Alkyl" means a branched or unbranched. saturated or unsaturated (i.e. alkenyl. a 1 kyiiylI aliphatic hydrocarbon group, having up to 12 carbon atoms unless otherwise specified. When used as part 3 a (followed by page 6) WO 20II8/II7V7J5 PCT/ljS2»l»?/l«?532 of another term, for example "alkylainino", the aikyl portion may be a saturated hydrocarbon chain, however also includes unsaturated hydrocarbon carbon chains such as "alkenyl am ino" and "alky ny lam ino. Examples of particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, ten-butyl, n-pentyl, 2-methv [butyl, 2,2-dim ethyl propyl, n-hexyl, 2-5 methylpentyl, 2,2-dimethylbutyl, n-heptyl. 3-heptyl, 2-methyIhexyl, and the like. The terms 'lower alkyl" "C;-C4 alkyl" and "alkyl of I to 4 carbon atoms" are synonymous and used interchangeably to mean methyl, ethyl, 1-propyl, isopropyl, cyclopropyl, 1-butyl, sec-butyl or t-bulyL Unless specified, substituted, alkyl groups may contain one, for example wo, three or four substitnents which may be the same or different. Examples of substituents are, unless otherwise 10 defined, halogen, amino, hydroxyl, protected hydroxyl, mercapto, carboxy, alkoxy, nitro, cyano, amidino, guanidino, urea, sulfonyl, sulfmyl, aminosulfonvl, alkylsulfonylamino, arylsulfonylaniino, aminocarbonyl, acylamino, alkoxy, acyl, acyloxy, a carbocycle, a heteroeyele. Examples of the above substituted alkyl groups include, but are not limited to; cyanomethyl, nitro methyl, hydroxymethyl, trityloxymcthyl, propionyloxy methyl, aminormethyl, carboxymethyl, IS earboxyethyl, carboxy propyl, alkykwycarbonylmethyl, ;> I ly I oxycarbony lam in ome.thy 1, carbamoyloxymethyl, methoxymethyl, ethoxyinethyl, t-but oxy methyl, acetoxymethyi, chloromethyl, bromomethyl, iodomethyl, trifiuoromethyl, 6-hydroxyhexvl, 2,4~dicbloro(n-butyl), 2-arnino(iso-propyl), 2-carbamoyloxyethyl and the like. The alkyl group may also be substituted with a carbocycle group. Examples include cyclopropylmefhyl, cyclobutylmethyl, 20 cyclopenty I methyl, and cyclohexylmethyl groups, as well as the corresponding -ethyl, -propyl, -butyl, -pentyl, -bexyl groups, etc. Substituted alky Is include substituted methyls e.g. a methyl group substituted by the same substituents as the "substituted Cr)-C„; alkyl" group. Examples of the substituted methyl group include groups such as hydroxy methyl, protected hydroxy methyl (e.g. tetTahydropyranyloxymethyl), acetoxymethyi, carbamoyloxymethyl, trifiuoromethyl, 25 chloromethyl, carboxymethyl, bromomethyl and iodomethyl. "Amidine" means the group -C(NH)-NHR in which R is H, alkyl, a carbocycle, a heteroeyele, carbocycle-substituted alkyl or heterocy c 1 e-subsii t uted alkyl where in the alkyl, alkoxy, carbocycle and heteroeyele are as defined herein. A particular amidine is the group -NH-C(NH)-30 NH2. "Amino" means primary (i.e. -NH2), secondary (i.e. NRH) and tertiary (i.e. NRR) amities in which R is H, alkyl, a carbocycle, a heteroeyele, carbocycle-substituted alkyl or heterocycle-snbstituted alkyl wherein the alkyl, alkoxy, carbocycle and heteroeyele are as defined herein . 35 Particular secondary and tertian' amines are alkylamine, dia Iky lam ine, any lam me, diary lam ine, ara Iky lam ine and diaralkylamine wherein the alkyl is as herein defined and optionally 6 WO 2008/07V7J5 PCT/ljS2(ll»?/l«?532 substituted. Particular secondary and tertiary amines are metbylami.ie, ethylamme, propylamine, isopropylamine, phenylamine, benzy (amine dimethylamme, diethyl am ine, di propylamine and d isopropylamine. 5 "Amieo-protecting group" as used herein refers to a derivative of the groups commonly employed to block or protect an amino group while reactions are carried out on other functional groups on the compound. Examples of such protecting groups include carbamates, amides, alkyl and aryt groups, imines, as well as many N-heteroatom derivatives which can be removed to regenerate the desired amine group. Particular amino protecting groups are Boc, Fmoc and Cbz. 10 Further examples of these groups are found in T. W. Greene and P. G, M. Wuts, "Protective Groups in Organic Synthesis", 2'"" ed., John Wiley & Sons, Inc.. New York, NY, 1991, chapter ?; E, Haslam, "Protective Groups in Organic Chemistry", J. G. W. McOtnie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T.W, Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981. The term "protected amino" refers to an amino 15 group substituted with one of the above ammo-protecting groups. "Aryl" when used alone or as part of another term means a carbocyclie aromatic group whether or not fused having the number of carbon atoms designated or if no number is designated, up to 14 carbon atoms. Particular aryl groups are phenyl, naphthyl, biphenyl, phenanthrenyl, 20 naphthacenyl, and the like (see e.g. Lang's Handbook of Chemistry (Dean, J, A,, ed) 13d' ed, Table 7-2 [1985]), A particular aryl is phenyl. Substituted phenyl or substituted aryl means a phenyl group or aryl group substituted with one, two, three, four or five, for example 1-2, 1-3 or 1-4 substituents chosen, unless otherwise specified, from halogen (F, CI, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (for example C«-C6 alkyl), alkoxy (for example CrC6 25 alkoxy). benzyloxy, carboxy, protected earboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifiuoromethyl, alkylsulfonylamino, al ky Isu Ifony lam in oaiky 1, arylsulfonylamino, ary Isu lotiy lam inoal kyl, heteroeyclylsulfonylammo, heterocyclylsulfonylaminoalkyl, heterocyclyl, aryl, or other groups specified. One or more methyne (CH) and/or methylene 30 (CHj) groups in these substituents may in turn be substituted with a similar group as those denoted above. Examples of the term "substituted phenyl" includes but is not limited to a mono-or dt(halo)pheny) group such as 2-chlorophenyl, 2-bromophenyl, 4-ehlorophenyl, 2,6-dichlorophenyl, 2,5-dichIorophenyI, 3,4-diehlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyI, 3-chloro-4-fluoropheny1, 2-fl uoropheny 1 and the like; a 35 mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxy phenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group 7 WO 20II8/II7V7J5 PCT/ljS2»l»7/l«?532 such as 3- or 4-nifrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono- or di((ower alkyl)phenyl group such as 4-rnetbyIphenyI, 2,4-di methy (phenyl, 2-methyIphenyl, 4-(iso-propyl)plienyl, 4-ethy(phenyl, 3-(n-propyI)phenyI and the like; a mono or di(a(koxy)phenyl group, for example, 3,4-dimethoxyphenyl, 3 -m ethoxy-4-berizyloxypheny1, 3-methoxy-4-(l-5 ehloromethy()benzyloxy-pheoyt 3-ethoxyphenyl, 4-(isopropoxy)pheny 1, 4- (t-butoxy)pheny I, 3-etboxy-4-metho xy phenyl and the like; 3- or 4- tri fi u oromethy Iph eny I; a mono- or dicarboxyphenyl or (protected carboxy)pheny( group such 4-carboxyphenyl, : a mono- or d ((hydroxy methy l)pheny 1 or (protected hydroxy methy I )pheny I such as 3-(protected hydroxy methy ()pheny( or 3,4 -d i(hy droxy methy l)pheny I; a mono- or di(am inomethy ()pheny( or 10 (protected am inomethy l)pheny( such as 2-{am inomethy IJphenyl or 2,4-(protected am(nomethyI)pheny 1; or a mono- or di(N-{methylsulfotwlaniino))plienyl such as 3-(N-methyIsu)fonvlammo))phenyI. Also, the term "substituted phenyl" represents disubstitiited phenyl groups where the substituents are different, for example, 3-methy 1-4-hydroxypheny 1, 3-ch loro-4-hydroxypheny 1, 2-m ethoxy -4-bromopheny 1, 4 -ethy 1 -2-hvdroxy pheny 1, 3 -hydroxy-4-15 nitrophenyl, 2-hydroxy-4-chlorophenyl, and the like, as well as trisubsti Luted phenyl groups where the substituents are different, for example 3 -methoxy-4- benzy loxy-6-methy 1 sulfonylamiiio, 3 -m et hoxy-4-be nzy loxy-6-pheny 1 sulfony (amino, and tetrasubstituted phenyl groups where the substituents are different such as 3 -methoxy-4 -benzy loxy - 5 -m ethy 1 -6-pli eny 1 sulfony (amino. Particular substituted phenyl groups include the 2-cblorophenyI, 2-aminophenyl, 20 2-bromophenyt, 3-methoxyphenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyi, 4-methoxyphenyl, 3-ethoxy-4-benzy loxy pheny I, 3,4-diethoxypheny I, 3 -methoxy-4-benzy loxy ph eny I, 3-methoxy-4-(1 -ch loromcthy I )benzy loxy -pheny I, 3-meth oxy-4 -(1 -ch I oromethy l)benzy loxy -6- m ethy I sulfony I aminophcnyl groups, fused aryl rings may also be substituted with any, for example 1, 2 or 3, of the substituents specified herein in the same manner as substituted alkyl groups. 25 "Carbocyclyl", "carbocyclylic", "carbocycle" and "carbocyclo" alone and when used as a moiety in a complex group such as a carbocycloalkyl group, refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms, for example 3 to 7 carbon atoms, which may be saturated or unsaturated, aromatic or non-aromatic. Particular saturated carbocydie groups are 30 cyclopropyl, cyclobutyl, cyclopentyl and cyciohexvl groups. A particular saturated carbocycle is cyclopropyl. Another particular saturated carbocycle is cyclohexyi. Particular unsaturated carbocycles are aromatic e.g. aryl groups as previously defined, for example phenyl. The terms "substituted carbocyclyl", "carbocycle" and "carbocyclo" mean these groups substituted by the same substituents as the "substituted alkyl" group, 35 I WO 2008/07V7J5 PCT/ljS2»l»7/l«?532 "Carboxy-protecting group" as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include 4-nitrobenzyt, 4-methoxybertzyl, 3,4-dimethoxy benzyl, 2,4-5 dimethoxy benzyl, 2,4,6-triinethoxy benzyl, 2,4,6-trimethyl benzyl, pen tamethy I benzy 1, 3,4-methylened ioxyben zy 1, benzhydryL 4,4' -dimeth oxybenzhyd ry 1, 2,2 ',4,45 - tetramethoxybenzhy dry I, alkyl such as t-butyl or t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4' ,4"-trimethoxy trity 1, 2-phenylprop-2-yl, trim ethy Isilyl, t-buty Id i methy Isilyl, phenacyl, 2,2,2-trichloroethyl, beta-(trimethy!siiyl)ertiyl, beta-(di(n-butyl )methy Isily 1 )ethy 1, p-10 to luenesul fony lethy 1, 4-nitrobenzy Isu Ifony lethy I, allyl, cinnaniyl, 1 -(trimethy Isilyl methy l)prop-I-en-3-yl, and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent react!on(s) on other positions of die molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. In particular, it is important not tc subject a carboxv-protected 15 molecule to strong nucleophilic bases, such as lithium hydroxide or Na()I-l, or reductive conditions employing highly activated metal hydrides such as Li AIR-.. (Such harsh removal conditions are also to be avoided when removing ammo-protecting groups and hydroxy-protecting groups, discussed below,) Particular carboxylic acid protecting groups are the alkyl (e.g. methyl, ethyl, t-butyl), allyl, benzyl and p-nitrobenzyl groups Similar carboxy-protecting 20 groups used in the cephalosporin, penicillin and peptide, arts can also be used to protect a carboxy group substituents. Further examples of these groups are found in T. W, Greene and P G, M. Wuts, "Protective Groups in Organic Synthesis", 2nd ed., John Wiley & Sons, Inc., New York, N.Y., 1991, chapter 5; E. Haslam, "Protective Groups in Organic Chemistry'*, J. G. W. McOtnie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T.W. Greene, "Protective 25 Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981, Chapter 5. The term "protected carboxy" refers to a carboxy group substituted with one of the above carboxy-protecting groups. "Guaniditie" means the group -NH-C(NH)-NUR in which R is H, alkyl a carbocycle, a 3© heteroeyele, carbocycle-substituted alkyl or heterocycle-snbstituted alkyl wherein the alkyl, alkoxy, carbocycle and heteroeyele are as defined herein. A particular guanidine is the group -NH-C(NH)-NHj. "Hydroxy-protacting group" as used herein refers to a derivative of the hydroxy group 35 commonly employed to block or protect the hydroxy group while reactions are carried out on other functional groups on the compound. Examples of such protecting groups include 9 WO 2008/07V7J5 PCT/ljS2»l»7/l«?532 tetrahydropy rany loxy, benzoyl, acetoxy, carbamoyloxy, benzyl, and si ly let hers (e.g. TBS, TBDPS) groups. Further examples of these groups are found in T, W. Greene and P. G, M. Wuts, "Protective Groups in Organic Synthesis'", 2nd ed., John Wiley & Sons, Inc., New York, "NY, 1991, chapters 2-3; E. Maslam, "Protective Groups in Organic Chemistry". J. G. W. 5 MeOmie, Ed.. Plenum Press, New York, NY, 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis". John Wiley and Sons, New York, NY, 1981. The term "protected hydroxy" refers to a hydroxy group substituted with one of the above hydroxy-protecting groups. 10 "Heterocyclic group", "heterocyclic", "heteroeyele", "heterocyclyl", or "heterocyclo" alone and when used as a moiety in a complex group such as a heterocycloalkyl group, are used interchangeably and refer to any mono-, bi-, or tricyclic, saturated or unsaturated, aromatic (Iieteroaryl) or non-aromatic ring having the number of atoms designated, generally from 5 to about 14 ring atoms, where the ring atoms are carbon and at least one heteroatorn (nitrogen, sulfur 15 or oxygen), for example. 1 to 4 heteroatorns. Typically, a 5-memhered ring has 0 to 2 double bonds and 6- or 7-membered ring has 0 to 3 double bonds and the nitrogen or sulfur heteroatorns may optionally be oxidized (e.g. SO, SO;), and any nitrogen heteroatorn may optionally be quatemized. Particular non-aromatic heterocyclics are morpholinyl (morpholino), pyrrolidinyl, oxiranyl. oxetanyi, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2H-pyranyl, tetrahydropy ranyl, 2© thiiranyl, th tetany 1, tetrahydroth tetany I, aziridinyl, azetidinyl, I -methyl-2-pyrrolyl, piperazinyl and piperidltiyl, A "heterocycloalkyP' group is a heteroeyele group as defined above covalently bonded to an alkyl group as defined above. Particular 5-membered heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, in panicular thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, in particular l,3,4-fniadiazoI-5-yl and 1,2,4-thiadiazol-5-y 1, 25 oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yI, and 1,2,4-oxadiazol-5-yl. Particular 5-tnembered ring heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl, triazolyl, such as l,3,4-triazol-5-yl; l,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as lH-tctrazol-5-yl, Particular benzo-fused 5-membered heterocycles are benzoxazol-2-yi, benzthiazol-2-yl and benzimidazol-2-yl. Particular 6-3© membered heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yt, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimld-4-yl; triazinvl, such as l,3,4-triazin-2-yl and 1,3.5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl. pyrimtd-4-yl, pyridazinyl and the l,3,4-triazin-2-yl groups, 35 are a particular group. Substituents for "optionally substituted heterocycles", and further examples of the 5- and 6-membered ring systems discussed above can be found in W. 10 WO 2008/07V7J5 PCT/ljS2»l»7/l«?S32 Druckheimer et at, U.S. Patent No. 4,278,793- In a particular embodiment, such optionally substittuted heteroeyele groups are substituted with hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxy 1, acyl, halo-substituted alkyl, amino, cyano, nitro. amidino and guanidino. 5 "Heteroaryi" alone and when used as a moiety in a complex group such as a heteroaralkyl group, refers to any mono-, bi-, or tricyclic aromatic ring system having the number of atoms designated where at least one ring is a 5-. 6- or 7-membered ring containing from one to four heteroatorns selected from the group nitrogen, oxygen, and sulfur, and in a particular 10 embodiment at least one heteroatorn is nitrogen (Lang's Handbook of Chemistry, supra). Included in the definition are any bicyclic groups where any of the above heteroaryi rings are fused to a benzene ring, Particular heteroaryls incorporate a nitrogen or oxygen heteroatorn. The following ring systems are examples of the heteroaryi (whether substituted or unsubstituted) groups denoted by the term "heteroaryi": thienyl, furyl, imidazolyl, pyrazolyl, Ihiazolyl, IS isotliiazolyl, oxazolyl, isoxazoiyl triazolyl, thiadiazolvl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazimyl, dithiazinyl. dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl. dihydropyrimidyi, tetrahydropy rim idyl, tetrazolofl ,5-bjpyridazinyl and purinyl, as well as benzo-fiised derivatives, for example benzoxazolyl, 20 benzofuryl, benzothiazolyl, benzothiadiazolyl, beezotriazolyl, benzoimidazolyl and indolyl, A particular ''heteroaryi" is: lJ-thiazol-2-yI, 4-(carboxymethyl)-5-methy 1-1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methy 1-1,3-thiazo 1-2-y 1 sodium salt, l,2,4-thiadiazol-5-vl, 3-methy 1-1,2,4-thiadiazoI-5-yl, 1,3,4-trtazol-5-yl. 2-methyl-l,3,4-iriazol-5-yf, 2-hydroxy-),3,4-triazol-5-yl, 2-carboxy-4-methy 1-1,3,4-triazo 1-5-yI sodium salt, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 1,3-25 oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 2-methyl-I,3,4-oxadiazol-5-yl, 2-(hydroxymethyl)-l,3,4-oxadiazol-5-yl, l,2,4-oxadiazol-5-yl» l,3,4-thiadiazol-5-yl, 2-tHol-1,3,4-thiadiazol-5-yL 2-(metbylthio)-1,3,4-thiadiazol-5-yl, 2-ammo-1,3,4-thiadiazol-5-yI, 1 H-tetrazol-5-yl, 1 -mefhyl-1 H-tetrazoI-5-yl. I-( 1 -(dimethy lamino)eth-2-y 1)-1 H-tetrazol-5-yl, I - (carboxymethyl)-1H-tetrazoI-5-yl, 1 -(carboxymethyl)-1 H-tctrazol-5-y I sodium salt, I-(methy(sulfonic acid)-lH-30 tetrazoI-5-yl, 1-(methy{sulfonic acid)- lH-tefrazol-5-yl sodium salt, 2-methy 1-1 H-tetrazol-5-yI. 1,2,3 -tr iazo 1-5-y 1, 1-methyl-1,2,3-triazoI-5-yl 2-methyl-1,2,3-triazol-5-yl, 4-methyI-1,2,3-triazol-5-yl, pyrid-2-yl IN-oxide, 6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-y 1, 1-methyIpyrid-2-yl, 1 -methylpyrid-4-yl, 2-liydroxypyrimid-4-yl, 1,4,5,6-tetrahydro-5,6-dioxo-4-methy l-as-triazin-3-y 1, 1,4.5,6 -tetrahy dro-4-( formy Imethy I )-5,6-d ioxo-as-tr i azin-3 -y J, 2,5-35 dihydro-5-oxo-6-hydroxy-astriazin-3-y1, 2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yI sodium salt, 2,5 - d i hy dro-5 -oxo-6-hy droxy-2- methy I - astriazin- 3 -y I sodium salt, 2,5-dihydro-5-oxo-6- 11 WO 2008/07V7J5 PCT/ljS2»l»7/l«?532 hydroxy-2-mcthy l-as-triazm-3 -y 1, 2,5-dihy dro-5-oxo-6-meth oxy-2-methy 1 -as-t riaztn-3 -y 1, 2,5-dihydro-S-oxo-as-triazin-3-yi, 2,5-dihydro-5-oxo-2-methyI -as-triazin-3-y1, 2,5-dihydro-5-oxo-2,6-dimethy l-as-triazin-3 -y I, tetrazolof l,5-b]pyridazin-6-yl and 8-aminotetrazolo[ 1,5-b]- pyridazin-S-yl, An alternative group of "heteroaryi" includes; 4-(carboxymethyl)-5-methyl-1,3-5 thiazol-2-yl, 4-(carboxymethy 1)-5-methy I -1,3-th iazol-2-yI sodium salt l,3,4-triazol-5-yl, 2-methyI-1,3,4-triazol-5-yI, lH-tetiazol-5-yI, 1-methyl-1 H-tetrazol-5-yl, 1 -{1 -(dimethylamino)eth-2-yl)-1 H-tetrazol-5-y I, 1 -(carboxymethyl)-1 H-letrazol-5-yl, 1 -(carboxymethyl)-1 H-tetrazol-5-y I sodium salt, 1 -(methy{sulfonic acid)-lH-tetrazol-5-yL 1-(niethyIsulforiic acid)-1 H-tetrazol-5-yl sodium salt, l,2,3-triazoi-5-yl, 1,4,5,6-tetrahy dro-5,6-dioxo-4-methyI-as-triazin-3-y I, 1.4,5,6-0 tetrahydro-4 -42-formy Im ethy l)-5,6-d i oxo-as-tri azi n- 3 -y 1, 2,5 -d ihy dro- 5 -oxo-6- hy droxy-2-methy I -as-tri azin-3 -y 1 sodium salt, 2,5-dihy dro-5-oxo-6-hydroxy-2-methy l-as-triazin-3 - vl, tetrazolof 1,5-b]py ridazin-6-y 1, and 8-aminotetrazolo[ 1,5-b]py ridazfc-6-y 1, Heteroaryi groups are optionally substituted as described for heterocycles. 5 "Inhibitor" means a compound which reduces or prevents the binding of IAP proteins to caspase proteins or which reduces or prevents the inhibition of apoptosis by an IAP protein, Alternatively, "inhibitor" means a compound which prevents the binding interaction of X-IAP with caspases or the binding interaction of ML-IAP with SMAC. 5 "Optionally substituted" unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e,g, 0, 1, 2, 3 or 4) of the substituents listed for that group in which said substituents may be the same or different. In an embodiment an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents, In another embodiment an optionally substituted group has 3 substituents, 5 " Pharmaceutical ly acceptable salts" include both acid and base addition salts, "Pharmaceutical!}-1 acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic 3 acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, eycloaliphatie, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, rnaleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, 5 einnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like. Received at IPONZ on 2 March 2012 "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts S of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trfmethylamme, diethylamine, triethylamine, tripropylamine, efhanolamine, 2-diethylaminoethanol, triiuethamine, dicyclohexylamine, lysine, arginine, histidlne, caffeine, procaine, hydrabamine, choline, beta ine, ethylenediamine, glucosamine, ruethylgiucamine, theobromine, purines, piperizine, piperidine, N-10 etfaylpiperidine, polyamine resins and the like. Particularly organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine. "SulfonyP means a ^SGj-R group in which R is H, alkyl, a carbocycle, a heteroeyele, carbocycle-substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heteroeyele are 15 as defined herein. Particular sulfonyl groups are alkylsulfonyl (i.e. -SOralkyl), for example methylsulfonyi; arylsulfonyl, for example phenylsulfonyl; aralkylsulfonyl, for example benzylsulfonyl. The phrase "and salts and solvates thereof as used herein means that compounds of the inventions may exist In one or a mixture of salts and solvate forms. For example a compound of the invention may be 20 substantially pure in one particular salt or solvate form or else may be mixtures of two or more salt of solvate forms. Z is H, alkyl, a carbocycle or a heteroeyele; wherein said alkyl, carbocycle and heteroeyele is optionally substituted with one or more hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, optionally substituted alkyl, amino, cyano, nitro, amidino, guanidino, an optionally substituted carbocycle 30 or an optionally substituted heteroeyele; and wherein one or more Cllj or CH groups of an alkyl is optionally replaced with -0-, -S-, -S(0}-, S(0)2, -N(R*)-, -C(O)-, -QOl-NRr, -NRg-QO)-, -SOj-NRr, -NRg-SOr, -NR«-C(0)-NR«-, -NRrC(NH)-NRr, -NRj-C(NH)-, -C(0}-0- or -O-C(O)-; The present invention provides a compound of formula (I): Ri I 25 wherein Xt and Xj are each independently O or S; Y is Ofc 13 (followed by page 13a) Received at IPONZ on 2 March 2012 Q is II. halogen. hydroxyl. carboxyl, ammo, nitro, cyano, alkyl. a carbocycle or a heteroeyele; wherem said aikyi. earbocyelc and heteroeyele is optionally substituted with one or more hydio.xyl, alkmv. acyl. halogen. mercapio, oxo. carboxvi, acyl. optionally substituted alkyi. amnm, cyano. nilro. amidino, gmmidino, an optionally substituted carbo.c.vcle sir an optionally substituted heteroeyele; and wherein one 5 or more Cll;.< or C'li tiroup.s of an aikyi is optionally replaced with 4)-, -S-, -S(t))-, S(0)>, -N(Rt;)^ -C(0|--, -C{0)-NR*-. -NR>-C{Ok -SOrNR,-. *N'R»-S()?-. -Nt^-("(0')-NRs-. -NRk-CCNIU-NR*-, -NRyONII)-. -UU)-0 o.r -0-C«.>i-. R, is 11. R~ s> mo.s p.intlsoo oi eve'ohexvl; 10 R; is methyl; R-< is ! I: R; is nu'thvi. ill" ts H. R.. is H: 15 R.:. ana R(-.' a.re each If. R, i.-< II. cyano. hydroxyl. mercapto, halogen, nitro, carboxy). amidmo. guanidino. alkyl, a carbocycle, a heleroeycle or 4 A . uherein IJ is -O-. -SlO)-, S(0)?. -N(RS)-, -C(0'K -C'(0)-NRs-. -NE.-Ctt'K -SO.-NRv-. -NR>-SO|-, • NRt-CtO)-NR»-. -NRx-QNIM-NR*-, -NJVC(N'H)-, -C(0)-0- or C(0}- and Y is alkyi, a carbocycle or a heteroeyele: and wherein one or more CH? or CH groups of an 20 alkyl i* epitonalh replaced with -0% -S-. -S(0K S{0)j. -NIRsK -QOK -C(C.))-NRS-. -NRh-C(0)-. -S0r NR>~. -NR.-S0J-. -NR;-O0»-NRr-. -C(0)-0- or -O-C(G)-; and an alkyl, carbocycle and heteroeyele is optionally substituted with hydroxy!. alkoxy, aeyl. halogen, mercapto, oxo. carboxyl, acyl, halo-substmned alkyl, ammo, cyano nitro. amidico. guanidino. an optionally substituted carbocycle or an optionally substituted hetcrocycie: 25 R,; is H, alkyl. a carbocycle or a heteroeyele wherein one or more CH-; or CH groups of said alkyl is optionally replaced with -0-, -S-, -SCO)-, 5fO)>. or -C(O)-: and said alkyl, carbocycle and heteroeyele is optionally substituted with hydroxyl. alkoxy. acyl, halogen, mercapto, oxo (-0), carboxyl, acyl, halo-substituted alkyl. amino, cyano nitro. amidino. guanidino. an optionally substituted carbocycle or an optionally substituted heteroeyele; and 30 111 is 0 to -5; wherein, for each occurrence, alkyl is independently a branched or unbranched, saturated or unsaturated aliphatic hydrocarbon: or a salt or stereoisomer thereof. 13a (followed by page 13b) Received at IPONZ on 2 March 2012 Al.sn ikscnlxvi are compounds basing the general formula la. R ; x, r2 'N,.\ N' Rr, , -Y A /k:p6 'V Kfi x2 //""n N /) jr-Q 13b {followed by page 14) WO 20II8/II7V7J5 PCT/ljS2»l»?/l«?532 wherein Q, Xb X2j Y, Z. Rb R2, R3, R3', Rj, Hi', R:„ R^.. R*' and ri are as described herein. Compounds of the invention include salts, solvates and polymorphs thereof unless otherwise specified. 5 Xi and X:- are each independently O or S. In a particular embodiment, X, and X-> are both 0. In another particular embodiment X, and Xj are both S. in another particular embodiment, Xj is S while X2 is O. In another particular embodiment, Xj is O while X2 is Y is a bond, (CRtRtXk O or S. In an embodiment Y is a bond, (CR7R;)m, O or S; wherein m is 1 H or 2 and R7 is as defined herein or is H, halogen, alkyl, aryi, aralkyl, amino, arylamino, alkylamino, aralkylamino, alkoxy, aryloxy or ara Iky loxy. In a particular embodiment, Y is (CHR-/)rn, O or S; wherein m is 1 or 2 and R? is H, halogen, alkyl, aryl, aralkyl, amino, arylamino, alkyiammo, aralkylamino, alkoxy, aryloxy or aralkyfoxy. fn a particular embodiment, V is CH2, In a particular embodiment m is 1. fn a particular embodiment Y is a bond. In a particular 15 embodiment m is I and Y is CHR? wherein R7 is aralkyloxv, for example benzyloxv. In a particular embodiment m is 1 and Y is CHR? wherein R7 is F. In a particular embodiment in is 1 and Y is CHR7 wherein R? is aralkylamino, for example benzy (amino. In another particular embodiment Y is O. In another particular embodiment Y is S. 20 2 is H, halogen, hydroxyl, carboxyl, amino, nitro, cyano, alkyl, a carbocycle or a heteroeyele; wherein said alkyl, carbocycle and heteroeyele is optionally substituted with one or more hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, optionally substituted alkvl, amino, cyano, nitro, amidino, guanidino an optionally substituted carbocycle or an optionally substituted heteroeyele; and wherein one or more Cf-I2 or CH groups of an alkyl is optionally 25 replaced with -O-, ~S^, -S(Oh 8(0),, -N(R8)-, -C(0>, -C(0)-NR8-, -NRrC(0)-, -SCVNRr, ■ NRt-SCV, -NRrC(0)-NRs-, -NRS-C{NH>NR*-, -NRrC(NII)-, -C<0)~0- or -O-C(O)-. In an embodiment Z is H, halogen, hydroxyl, carboxyl, amino, nitro, alkyl, a carbocycle or a heteroeyele wherein said alkyl, carbocycle and heteroeyele are optionally substituted with halogen, hydroxyl, carboxyl, amino, and nitro. In an embodiment Z is H, halogen or alkyl. In an 30 embodiment Z is H. In an embodiment Z is alkyi. for example methyl, ethyl, propyl and isopropyl. In an embodiment Z is phenyl or naphthyl. Q is H, halogen, hydroxyl, carboxyl, amino, nitro, cyano, alkyi, a carbocycle or a heteroeyele; wherein said alkyl, carbocycle and heteroeyele is optionally substituted with one or more 35 hydroxyl, alkoxy, acyl. halogen, mercapto, oxo, carboxyl, acyl, optionally substituted alkyl, amino, cyano, nitro, amidino, guanidino an optionally substituted carbocycle or an optionally 14 WO 2008/07V7J5 PCT/ljS2»l»?/»8?532 substituted heteroeyele; and wherein one or more CH2 or CH groups of an alky! is optionally replaced with -O-, -S-, -S(O)-, S(0)2, -N(R8)-, -C(0>, -C{0)-NRg-, -NRs-CfO)-, -SC32-NRr, -NRg-SCV, -NRg-C{0)-NRs-, -NRrC(NB)-NRg-, -NRs-C(NH)-, -C(0>0- or -O-C(O)-. Substituents of the "optionally substituted alkyi", "optionally substituted carbocycle" and 5 ''optionally substituted heteroeyele" are substituted as the foregoing alkyl, carbocycle and heteroeyele groups in Q, In a particular embodiment substituents of such "optionally substituted alkyl" are hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, amino, cyano, nitro, amidino and guanidino. In a particular embodiment such optionally substituted carbocycle and heteroeyele groups are substituted with hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo, 1© carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino and guanidino. In a particular embodiment Q is a carbocycle or heteroeyele optionally substituted with halogen, amino, oxo, alkyl, a carbocycle or a heteroeyele; wherein one or more CH2 or CH groups of an alkyl is optionally replaced with -O-, -S-, -S(0)-. SfO)?, -N(R8)-, -C(O)-, -C(€))-NR8-, -NRs-C(0)-, -SOrNRg-, -NRg-SOr, -NRyC(0)-NRr, -NR«-C(NHVNRS-, -NRrC(NH)-, -C(0)-0- or -O-JS C(O)-; and wherein said alkyl, carbocycle or heteroeyele is optionally substituted with halogen, amino, hydroxyl, mercapto, carboxyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, alkylthio, acyloxy, acyl oxy alkoxy, alky Isu Ifonyl, alkylsulfonylalkyl, alkylsulftnyl, and alkylsulfinylalkyl. In a particular embodiment Q is a carbocycle or a heteroeyele as defined herein which is optionally substituted as described herein while Z, is selected fi-om the group consisting of H, halogen, 20 carboxyl, amino, nitro and cyano. In a particular embodiment Q is aryl or heteroaryi while Z is selected from the group consisting of H, halogen, carboxyl, amino, nitro and cyano, In a particular embodiment Z is H, In another particular embodiment, such other instances of Z is H, halogen or alkyl 25 In a particular embodiment, Q is a carbocycle or heteroeyele selected from the group consisting of III-1 - 111-16 HI-1 111-2 III-3 01-4 15 WO 2008/07V7J5 PCT/ljS2»l»7/l«?532 (R?), (R?)n Hi-6 (R7)n III-8 "n III-9 1R?)n (R7)n {R?)n III- n A (R7)n 111-12 (R/)n ?<V -<R7)n N 111-14 n (R7)n J > n (Rr)n 111-16 10 wherein ti is 1-4, for example 1-3, for example 1-2, for example I; T is O, S, NRg or CR?R?; W is O, NRg or CR7R7, and R7 and rs are as defined herein. In an embodiment, Q has the general formulae III-1 to III-16 while Z is selected from the group consisting of H, halogen, carboxyl, amino, nitro and cyano. in a particular embodiment Z is l-L In another particular embodiment, Z Is II. halogen or alkyl, 15 20 In a particular embodiment, Q is a carbocycle or heteroeyele selected from the group consisting of Ilia - Ills: "(R7)r Rf Ilia O illb (R?)n lHR7)n / 1 lid 16 WO 2008/(17^735 PC'T/(JS20fl7/(l875J2 '(R?)n ' (R7)n llli ( ^7 )n Hli 10 -|-(R?)n 111k n » // N--N Hill "(R?)n 111/ N (Rr)„ IIIo (R?)n (R?5n Hip 15 (R?Sn lllq IHr / -N \ J N wherein n is 1-4, for example 1-3, for example 1-2,, for example 1; I is O, S, NRS or CR?R?; W is 0, NRg or CR7R7, and R7 and R8 are as defined herein, In a particular embodiment Q is any one 17 WO 20II8/II7V7J5 PCT/ljS2»l»?/l«?532 of Ilia - [Hi wherein Re is H and R- is selected from the group consisting of H, F, CI, Me, methoxy, hydroxyethoxy, methoxy ethoxy, acetoxyethoxy, methy 1 sulfony] methyIsulfonyImethyi, phenyl and morpholin-4-yl. In another particular embodiment Q is Hid. In a particular embodiment Q is Hid which is substituted at the 4-positioo with R?. In another particular 5 embodiment Q is Hid which is substituted al the 5-position with R- In a particular embodiment Q is P, Me, iPr, phenyl, phenyl substituted as follows: 2-CI, 3-Cl, 4-CI, 2-F, 3-F or 4-F substituted, benzyl, pyrid-3-yl or pyrid-4-yl, In an embodiment, Q has the general formulae IIla to Ills while Z is selected from the group consisting of II, halogen, carboxyl, amino, nitro and cyano. In a particular embodiment Z is B, In another particular embodiment, Z, is 11, halogen or 10 alkyl. Rt is H, OH or alkyl; or Rt and R2 together form a 5-8 member heteroeyele. In a particular embodiment, R| is II. In a particular embodiment, R and R2 together form a 6-memher ring. In a IS particular embodiment, R, and Rt together form a 7-member ring. In another particular embodiment, R( and R? together form an 8-member ring, In another particular embodiment, R. and R2 together form a 7-member ring while Y is S. In another particular embodiment, R, is 14, while y is CH2. In another particular embodiment, r| is H, while Y is S. In another particular embodiment. R; is H, while Y is O. 20 R2 is alkyl, a carbocycle, carbocyclylalkyl, a heteroeyele or heterocyclylalkyl each optionally substituted with halogen, hydroxyl, oxo, thioise, mercapto, carboxyl, alkyl, haloalkyl, acyl, alkoxy, alkylthio, sulfonyl, amino and nitro, wherein said alkyl, acyl, alkoxy, aikylthio and sulfony 1 are optionally substituted with hydroxy, mercapto, halogen, amino, alkoxy, 25 hydroxy alkoxy and alkoxy alkoxy. In an embodiment, R> is alkyl. a carbocycle, carbocyclylalkyl, a heteroeyele or heterocyclylalkyl each optionally substituted with halogen, hydroxyl, oxo, thione, mercapto, carboxyl, alkyl, haloalkyl, alkoxy, alkylthio, sulfonyl, amino and nitro. In a particular embodiment R2 is alkyl, a carbocycle, carbocyclylalkyl, a heteroeyele or heterocyclylalkyl each optionally substituted with halogen, hydroxyl, oxo, mercapto, thione, 30 carboxyl, alkyl, haloalkyl, alkoxy, acyl, alkylthio, acyl, hydroxy acyl, methoxy acyl sulfonyl, amino and nitro. In an embodiment R2 is alkyl, a carbocycle, carbocyclylalkyl, a heteroeyele or heterocyclylalkyl each optionally substituted with halogen, hydroxyl, mercapto, carboxyl, alkyl. alkoxy, acyl, amino and nitro, In a particular embodiment R2 is alkyl, cycloalkyl, eycloalkylalkyl, aryl, aralkyl, a heteroeyele or heterocyclylalkyl In a particular embodiment R;j is alkyl 35 cycloalkyl or a heteroeyele. In a particular embodiment R2 is selected from the group consisting of t-butyl, isopropyl, cyclohexyl, tetrahydropyran-4-yl, N-methy Isul fony lpiperidin-4-yl, 18 WO 2008/07V7J5 PCT/ljS2»l»?/l«?532 tetrahydrothiopyran-4-yI, tetrahydrothiopyran-4-yI (in which ihe S is in oxidized form SO or S02), cyclohexan-4-one, 4-hy d roxycy c I obex ane, 4- hy droxy-4-methy I cy c 1 ohexane, 1-methyl -tetrahy d ropy ran-4-yl 2-hy droxy prop-2-y I, but-2-yl, thiophen-3-yi, piper id in-4-v], N-acetylpiperidin-4-yI, N-hydroxyelhyipiperidi n-4-y1, N-(2-hydroxyacetyI jpiperid i n-4-y I N-(2-5 meth oxy acety 1 )pi perid i n-4-yI, pyridin-3-yI, phenyl, tetrahy d roftiran -2-y] -car bony 1, methoxvethanone, 2-methoxyetboxyetftanone and t-hydoxyeth-l-yl. In an embodiment of the invention R: is t-butyl, isopropyl, cyciohexyl, cyelopentyl, phenyl or tetrahy dropyran-4-yI. In a particular embodiment, R2 is phenyl, In a particular embodiment, R2 is cyciohexyl, In another embodiment R2 is tetrahy d ropy ran -4-y 1. In another particular embodiment, R. is isopropyl (i.e. 10 the valine amino acid side chain). In another particular embodiment, Rj is t-butyl. In a particular embodiment R2 is oriented such that the amino acid, or amino acid analogue, which it comprises is in the L-configuration. Il3 is It or alkyl optionally substituted with halogen or hydroxyl; or R; and R., together form a 3-6 15 heteroeyele. In an embodiment Ri is H or alkyl; or R3 and R4 together form a 3-6 heteroeyele. In an embodiment R3 is H or methyl, ethyl, propyl or isopropyl. In a particularly particular embodiment Rj is H or methyl. In another particular embodiment R? is methyl. In another particular embodiment R: is fluoromethyl. In another particular embodiment, Rj is ethyl. In another particular embodiment R3 is hydroxy ethyl In a particular embodiment R:) is 20 fluoromethyl In a particular embodiment R? is hydroxyethyl. In another embodiment R3 is oriented such that the amino acid, or amino acid analogue, which it comprises is in the L-conflguration. In a particular embodiment Rj and R4 together with the atoms from which they depend form a 3-6 heteroeyele, In a particular embodiment Ri and R4 together form an azetidine ring. In a particular embodiment R3 and Ri together form a pyrrolidine, 25 R3' is H, or Rt and R?' together form a 3-6 carbocycle. In an embodiment, Ri' is H. In another embodiment R, and Ry together form a 3-6 carbocycle, for example a cyclopropyl ring. In a particular embodiment Rj and R-.' are both methyl. 30 R,» and I4* are independently H, hydroxyl. amino, alkyl, carbocycle, carbocycloalkyl, carbocyc I oalky loxy, carbocycloa Iky loxy carbony I, heteroeyele, h eterocyc loa Iky 1, heterocyc balky loxy or beterocy e loa I ky I oxy carbony 1; wherein each alkyl, carbocycloalkyl, carbocy cloalky loxy, carbocycl ©a Iky loxy carbony I, heterocyc le, h eterocy cloa Iky 1, heterocy cloalkyloxy and heterocycloalky loxy carbony! is optionally substituted with halogen, 35 hydroxyl, mercapto, carboxyl, alkyl alkoxy. amino, imino and nitro; or R4 and R.4' together form a heteroeyele. In an embodiment R4 and R.," are independently H, hydroxy!, amino, alkyl, aiyl, If WO 20II8/II7V7J5 PCT/ljS2»l»7/l«?532 aralkyl, cycloalkyl, cycloatkylalkyi, heteroaryi, or heteroarylalkyl wherein each alkyl, aryl, aralkyl, cycloalkyl, cyctoalkylaikyl, heteroaryi and heteroarylalkyl is optionally substituted with halogen, hydroxyl, mercapto, carboxyl, alkyl, alkoxy, amino and nitro; or R4 and R4' together form a heteroeyele. In a particular embodiment R,. and R,' together form a heteroeyele, for 5 example an azefidtne ring, or a pyrrolidine ring. In a particular embodiment Rj and RV are both H. In another particular embodiment R4 is methyl and IV is H In a particular embodiment one of Rj and R.f is hydroxyl (OH) while the other is H. In another embodiment, one of R* and IV is amino, such as NH2, NHMe and NHEt, while the other is H In a particular embodiment, R4* is H and R4 is H, alkyl, aryl, aralkyl, cycloalkyl, cycioalkylalkvl, heteroaryi or heteroarylalkyl. In a 10 particular embodiment M4 is a group selected from the group consisting of: 20 WO 2008/07V7J5 PCT/ljS2»l»7/l«?532 EIO HO' HO' I Br ,* HO / ^ N02 HO' '~no2 HN'-:" 5 Rs is H or alkyl. In a particular embodiment, Rj is H or methyl, In a particular embodiment, R5 is H, In another particular embodiment, R5 is meihvL 10 R6, and Rfi' are each independently HE, alkyl, aryl or aralkyl, In a particular embodiment, Rr. is alkyl, for example methyl . In another particular embodiment R<: is aryl, for example phenyl. In another particular embodiment R„ is aralkyl, for example benzyl. In a particular embodiment Rt and R6' are the same, for example both alkyl, e.g. both methyl. In another particular embodiment R6 is methyl and R6' is H, R7 in each occurrence is independently 11 cyano, hydroxyl, mercapto. halogen, nitro, carboxyl, amidino, guanidino, alkyl, a carbocycle. a heteroeyele or -U-V; wherein IJ is -O-, -S-, -S(O)-, S(0}2, -N(RS)-, -C(O)-. -C(0)-NRr, -NRt-C(0)-, -SOrNRr, -NRa-SOr, -NRs-C(0)-NRr, -NRg-C(NH)-NRS-, -NRg-C(NH)-, -C(0)-0- or -O-C(O)- and V is alkyl, a carbocycle or a heteroeyele; 20 and wherein one or more CH2 or CH groups of an alkyl is optionally replaced with -0-, -S-, -S{0)-, S{0)2, -N(Rg)-, -C(O)-, -C(0}-NRg-, -NR,-C(0)-, -SOrNRr, -NRr-SOr, -NRrC(0)-NRr , -HRs-C(NH>NR8-, -NR8-C{NH>, -C(0)-0- or -O-C(O)-; and an alkyl, carbocycle and heteroeyele is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino an optionally 25 substituted carbocycle or an optionally substituted heteroeyele. Substituents of the "optionally substituted carbocycle" and "optionally substituted heteroeyele" are as defined herein. In a particular embodiment such carbocycle and heteroeyele groups are substituted with hydroxy], alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano, 15 21 WO 2008/07V7J5 P€"T/1US20I»?/I»8?532 mtro, amidino and guanidino. In an embodiment R7 is H, halogen, alkyl, haloalkyl, aryl, aralkyl, amino, arylamino, alkylatnino, aralkylamino, alkoxy, alkoxy alkoxy, arytoxy or ara Iky loxy. Rs is H, alkyl, a carbocycle or a heteroeyele wherein one or more CH2 or CH groups of said alkyl is optionally replaced with -O-, -S-, -S(O)-, S(0)2, ~N(Rg), or -C(O)-; and said alkyl, carbocycle and heteroeyele is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo (=0), carboxyl, acyl, halo-substituted alkyl, amino, cyano nitro, amidino, guanidino an optionally substituted carbocycle or an optionally substituted heteroeyele. Substituents of the "optionally substituted carbocycle" and "optionally substituted heteroeyele" are as defined herein. In a particular embodiment such carbocycle and heteroeyele groups are substituted with hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino and guanidino. In a particular embodiment Rg is H, alkyl, or acyl. In an embodiment Rg is methyl. In another embodiment Rg is acetyl In a particular embodiment R« is H. In an embodiment R7 is II, halogen, amino, hydroxyl, carboxyl, alkyl, haloalkyl or aralkyl. In a particular embodiment R7 is halogen, for example CI or P. In a particular embodiment R. is H. It is understood that substitutions defined for R- and Rg as well as all other variable groups herein are subject to permissible valency. m is 0 to 4. In an embodiment m is 0. fn an embodiment m is 1. In an embodiment in is 2. In an embodiment m is 3. In an embodiment m is 4. Compounds of the invention contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers or mixtures thereof. The syntheses of the compounds may employ racemates, diastereomers or enantiomers as starting materials or as intermediates. Diastereomeric compounds may be separated by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated using the same techniques or others known in the art. Each of the asymmetric carbon atoms may be in the R or S configuration and both of these configurations are within the scope of the invention. In a particular embodiment, compounds of the invention have the following stereochemical configuration of formula I' 22 Received at IPONZ on 2 March 2012 w herein X:. X >. "S . O R;. RR R(. R (\ Rf, Rfl artel R,,' <irc as defined J or compounds ol I hi inula {1) oi she an ens ion. A No described are compounds of formula 1" wherein X:, X% Y, /. Q R.. Ri. R., R.,, R.,\ Rs Rfl and R,d ;:re as described herein for compounds of formula la. In pailieus;.!! embodimcnss, compounds of Use invention have the general Ibrrnula I la -lid r r. R. o . X, R:, V-V R, o • X1 R2 ) Y ■ N : : A ...N, ><dr'; >U.a .A >CR» R.1 i Rr ! \ 4 f Rn I: \ R3 " X2 /^N Ra X2 j N \ 'N"X f "> q % jr-z - lib r. R4 R • X, r2 Y-Y ^ i (Y Y Re K3 x2 l \ IR7)" (R-rfir-f / lie Z ■ IId W wherein X;, X:, Y, Z. Q R,. R2, R„ R4, R.,\ Rs, R6, RA" and R7 are as defined for compounds of formula (It of the indention Also described are compounds of formula Ila, lib, He, and lid wherein Xu X2, Y, Z, Q Ri, R?, Rj, R4. R4'. R>. R(.. R:.5 and R-are as described herein for compounds of formula la. Also described are prodrugs of the compounds described above. Suitable prodrugs where applicable include known ammo-protecting and carboxy-protecting groups which are released, for example hydroiyzed. to yield the parent compound under physiologic conditions. A particular class of prodrugs are compounds in which a nitrogen atom in an amino, amidino, aminoalkyleneamino, iiranoalkyieoeaniino or guanidino group is substituted with a hydroxy (OH) group, an alkylcarbonyl C-CO-R) group, an alkoxycarbonyl (-CO-OR), an acyloxyalkyI-alkoxycarbonyI (- CO-O-R-O-CO-R) group where R is a monovalera or divalent group and as defined above or a group having the formula -Q0)-0-CP 1 P2-haloalkyL where PI 23 (followed by page 23a) Received at IPONZ on 2 March 2012 and l'2 are she same or different and are If, lower alkyl. lower alkoxy. cyano, halo lower alkyl or ar\L In a parlicutar embodiment, ihe nitrogen atom is one of I he nitrogen atoms of the amidino group of Hie eon-pound.-, nf ihe invention, I'liese prodrug compounds are prepared reading die compounds o| she invenuori described alnnc wit it an activated acyl compound to bond a nitrogen 5 atom m t he compound of the invention to the carbony I of the activated acyl compound. Suitable activated carnonyl compounds contain a good leaving group bonded to the carbony I carbon attd include 23 a (followed by page 24) WO 2008/07V7J5 PCT/ljS2»l»7/l«?532 acyl halides, acyl amines, acyl pyridinium salts, acyl alkoxides, in particular acyl phenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl fluorophenoxv acyl, and difltiorophenoxy acyl. The reactions are generally exothermic and are carried out in inert solvents at reduced temperatures such as --78 to about 50C The reactions are usually also carried out in the presence of an 5 inorganic base such as potassium carbonate or sodium bicarbonate, or an organic base such as an amine, including pyridine, triethy (amine, etc, One manner of preparing prodrugs is described in USSN 08/843,369 filed April 15, 1997 (corresponding to PCI" publication W09846576) the contents of which are incorporated herein by reference in their entirety. 10 Particular compounds of formula I include the following: H H rt O V ANX,rO H I k >-\ OH 0 ± l_J :! \ fV \ L Vi w V'\ c -On jJLnJviQ ' H 6 > /"N .. HI h\ -C~y"J kj" HN—\ o jucy? N H /*~H ii Nr\ v/ -OH .0. h f f r\ H 6 KJ 0 „ ,N.rtAr>Q ° /"N N^- V-\ rt Y O J" u >JvCirN°2 ^ ir 24 WO 2008/079735 PCT/ljS2»l»?/»8?532 Y o rW v o 'Y r~\ AmAw'Ns/ 6 N-\ i „ V/ \--NHj o < r r^-\ N_'\ / t / V YA' \ J .N... ,A. 1 iQ N Y \-t -J H y\J H V .N^ A, xnA rv "N k // 1 r \ •N-W H O /-N V-» A/ /"N V ~VJ -Ok / ~N N"\ KV/ 9< W i/ WO 2008/07V7J5 PCT/ljS2»l»?/l«?532 Compounds of the invention may exist in different resonance forms and that all such resonance forms are within the scope of the invention herein, 5 SYNTHESIS Compounds of the invention are prepared using standard organic synthetic techniques from commercially available starting materials and reagents. It will be appreciated that synthetic 10 procedures employed in the preparation of compounds of the invention will depend on the particular substituents present in a compound and that various protection and deprotection steps that are standard in organic synthesis may be required but may not be illustrated in the following general schemes. In a particular general synthetic scheme, compounds of the invention may be prepared by coupling amino acid residue analogues employing typical amide coupling procedures. 15 In scheme I, wherein Q, Y, Z, Rb R(, and R«* are as defined herein and Pr is a suitable protecting group, ami tie-protected amino acid residue analogues are coupled and deprotected sequentially to give the final compounds. 26 WO 20II8/IHV7J5 PCT/US2007/087532 Scheme I h 1 n r zkJ^Q Ri Ri r2 v~X r4 o,. X1 R2 v-y vvs^§ ~R; r ^nVYYn^ 3- p R* i % | \ \/Kn,, 3 2 /^N N " 1 J R 5 X2 /^N >x\/^ Ka " A2 / . ( i rf Y OH \ I N \ 4 ^ N Z I J m ^ 7KJ^q 5 It will be appreciated that the amino acid analogs may be coupled in any order and may be prepared using solid phase support which is routine in the art. For example. Scheme 2 illustrates an alternative amino acid residue analogue coupling route. Scheme 2 Ft, Rj' x, Ra R\ R,1 f XlA + HKr'V-o-P' ■< Y OH H-N ~f T N f t0 ' R3 Rs RS 5 R, R1 ^4 R.' ¥1 ^2 N Y Ra O - Xj r2 V x K\ r3- f ? v-x D r3- *> ^ r\ o McV"+ M — /tVrY^ *^2 ' L R3 ~ A2 N-\ N / J q z\~r jr~Q 1 m idazo [ 1,2a]py r id ine intermediates may be prepared according to scheme 3 wherein Q, Y, Z, R|, R6 and IV are as defined herein, Starting bromine a is reacted with 2-aminopyridyI b to give 15 protected compound c which is subsequently deprotected to give intermediate d employed in synthesis of compounds of tlie invention. 27 WO 2 OtlS/l 171) 7 35 PC'T/ tj S 2 (II17/1187532 Compounds of the invention in which R* or R4* are otiier than H may be prepared according to standard organic chemistry techniques, for example by reductive ami nation in which a starting amino acid residue analog e.g. NH2-CH(R5)-C(0)-0H is reacted with a suitable aldehyde or ketone to give the desired R4 and li4' substituents. See scheme 4. The resulting IVRT substituted amino acid intermediate can then be conjugated to the next amino acid intermediate or the remainder of the compound using standard peptide coupling procedures. Scheme 4 9 R3" |1 KJaCNBHj UOH H20 A .3 if NaLNJohi 'p _!01iH,0 „ - R—N+V0B" — R^N H T I % AcOH H H L OH H Rj' I 1 HJ\ H;l H Rg' X, X, DMF 1 1 In a particular embodiment, alanine is reacted with 1 -methylindole-2-carboxaldehyde and reduced with sodium cyanoborohydride "dissolved in 1% HOAc/DMF to give the N-substituted alanine residue which may be used in preparing compounds of the invention, See scheme 5. Scheme 5 -HA H 0 0 NaCNBH, 1 0R* H2NAD1 OR' 1% AcOH. DMF Alternatively, the reductive ami nation procedure to introduce RA' substituents is the final step in the preparation of the compound. When compounds of the invention incorporate R4 or IV substituents other than H, they may also be prepared by substitution of a suitable acid intermediate which incoiporates a leaving group 28 WO 2008/07V7J5 PCT/ljS2»l»7/l«?532 with a desired amine. For example br-ch(rj)-c{0)-0h is substituted with an amine r4-nh2 or R<-NH-R/ according to scheme 6, r« / NH + b DMF OR Scheme 6 R4s X! XN / OR' Li OH H,0 R4 Xi \. Ra' " THF. H,0 / Rj' OH Alternatively, the substitution reaction introducing R4 or R4' substituents may be performed as a final step in the preparation of the compound as illustrated in scheme 7, R4 R'V Scheme 7 0 . x, R2 V-Y r3 1 r I VRe Ri nh + R ,N *3 Rs x2 ,0.x, r2 W n r3 I J J, XrR8 <s DMF R. r3 Rs x2 n / J W if J r-Q N \ / j) In a particular embodiment, the following amines used in schemes 6 and 7; nh, 15 CI ,nh2 ^nh2 ,NH, 29 WO 2008/07V7J5 PCT/ljS2»l»?/l«?532 nh2 nh2 '^nh2 nh2 ho h3c k och3 och3 CI nh2 ho—nh2 5 Compounds of the invention in which either Xi or X3 is sulfur, i.e. the compound incorporates a thioamide, may be prepared according to established organic chemistry techniques, for example, compounds in which X2 is sulfur can be prepared according to scheme 8 starting from an fmoc protected amino acid residue analog NHrCH(R.j)-COOH which is dissolved in THF and cooled to -~25"C, with addition of D1PEA fo(lowed by addition of isobutyichloroformate. After 10 minutes, the diamine, 4-nitrobenzene-l ,2-diamine, is added and tlie reaction mixture is continuously stirred at -25°C for 2 hours, then al room temperature overnight. THF is vacuumed off and the mixture is then subjected to flash chromatography using 50% EtOAc/Hexane to yield the product. The Fmoc-alanine derivative, phosphorus pentasuifide and sodium carbonate are mixed in THF and stirred overnight. The solution is concentrated and direct chromatography using 80% EtOAc/Hexane yields the activated thioalanine. The activated thioalanine and sodium nitrite are then mixed in acetic acid and diluted with H20, The resulting precipitant is filtered and dried to yield the product. The thioalanine is coupled to an A ring substitued proline amino acid residue analog by dissolving both in DMF. The thioamide product may then be deprotected with 20% PIP/DMA for 15 minutes and used to conjugate to the R^/R^-N-CCRsXRi'j-COOH. Alternatively the Fmoc-protected thioamide is first coupled to the A ring substituted proline amino acid residue analog followed by Fmoc deprotection and subsequent coupling to the r4/iv-r/r4'-N-C(rj)(rjJ)-COOH amino acid residue analog, Scheme 8 10 WO 20II8/II7V7J5 PC'T/ U S 2 0117/11« 7S32 s indications The compounds of the invention inhibit the binding of iap proteins to caspases, in particular x-1ap binding interaction with caspases 3 and 7. The compounds also inhibit the binding of ML-IAP to Sniac protein. Accordingly, the compounds of the invention are useful for inducing 10 apoptosis in cells or sensitizing ceils to apoptotic signals, in particular cancer cells. Compounds of the invention are useful for inducing apoptosis in cells that ovcrexpress IAP proteins. Alternatively, compounds of the invention are useful for inducing apoptosis in cells in which the mitochondrial apoptotic pathway is disrupted such that release of Sinac from ML-IAP proteins is inhibited, for example by up regulation of Be 1-2 or down regulation of Bax/Bak, More broadly, 15 the compounds can be used for the treatment of all cancer types which fail to undergo apoptosis. Examples of such cancer types include neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, familiar}' adenomatous polyposis carcinoma and hereditary tion-polyposts colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, long carcinoma, salivary gland carcinoma, gastric carcinoma, 20 adenocarcinoma, medullar}' thyroidea carcinoma, papillary thyroidea carcinoma, renal carcinoma, kidney parenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal 31 WO 2008/07V7J5 PCT/ljS2»<»7/»8?532 tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Bark in lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-eell leukemia lymphoma, hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung 5 carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, chore idea melanoma, seminoma, rhabdomyo sarcoma, cran iopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, Iiposarcoma, fibrosarcoma, Ewing sarcoma and plasmacytoma. Compounds of the invention are useful for sensitizing cells to apoptotic signals. Accordingly, the 1® compounds may be administered prior to, concomitantly with, or following administration of radiation therapy or cytostatic or antineoplastic chemotherapy. Suitable cytostatic chemotherapy compounds include, but are not limited to (i) antimetabolites, such as cytarabine, fludarabine, 5-fluoro-2' -deoxy ui rid ine, gemcitabine, hydroxyurea or methotrexate; (ii) DNA-fragmenting agents, such as bleomycin, (iii) DNA-cross linking agents, such as chlorambucil, cisp latin, 15 cyclophosphamide or nitrogen mustard; (iv) intercalating agents such as adriamycin (doxorubicin) or mitoxantrone; (v) protein synthesis inhibitors, such as L-asparagioase, cycloheximide, puromycin or diphtheria toxin; (Vi) topoisomerase 1 poisons, such as camptotbecin or topotecan; (vii) topoisomerase II poisons, such as etoposide (VP-16) or teniposide; (viii) microtubule-directed agents, such as colcemid, colchicine, padifaxel, vinblastine or vincristine; (ix) kinase 20 inhibitors such as flavopiridol, staurosporin, STI571 (CPG 57148B) or UCN-OI (7-hydroxystaurosporine); (x) miscellaneous investigational agents such as thioplatin, PS-341, phenyIbutyrate, ET-18- GCHj, or famesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetm, resveratrol, piceatannol, epigallocatechine gal late, theafiavins, flavanols, procyanidins, betulinic acid and derivatives thereof; (xi) hormones such as glucocorticoids or fenretinide; (xii) hormone antagonists, such as tamoxifen, finasteride or LHR.H antagonists. In a particular embodiment, compounds of the present invention are coadministered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere and mitomycin C. In a particular embodiment, the cytostatic compound is doxorubicin. 3# Another class of active compounds which can be used in the present invention are those which are able to sensitize for or induce apoptosis by binding to death receptors ("death receptor agonists"). Such agonists of death receptors include death receptor ligands such as tumor necrosis factor a (TNF-a), tumor necrosis factor 6 (TNF-fl, tymphotoxin-a) , LT-fi (lymphotoxin-B), TRAIL (Apo2L, DR4 ligand), CD95 (fas, APO-l) ligand, TRAMP (DR3, Apo-3) ligand, DR6 ligand as 35 well as fragments and derivatives of any of said ligands. In an embodiment, the death receptor 32 WO 2OtlS/ll7V735 PC*T/ U S20117/11875J 2 ligand is TNP-ct In a particular embodiment, the death receptor ligand is Apo2L/TRAIL. furthermore, death receptors agonists comprise agonistic antibodies to death receptors such as anti-CD95 antibody, anti-TRAJL-Rl (DR4) antibody, anti-TRAlL-R2 (DR5) antibody, anti-TRA1L-R3 antibody, antt-TRAIL-R4 antibody, anti-DR6 antibody, anti-TNF-RI antibody and 5 anti-TRAMP (DR3) antibody as well as fragments and derivatives of any of said antibodies. For the purpose of sensitizing cells for apoptosis, the compounds of the present invention can be also used in combination with radiation therapy- The phrase "radiation therapy" refers to the use of electromagnetic or particulate radiation in the treatment of neoplasia, Radiation therapy is based on foe principle that high-dose radiation delivered to a target area will result in the death of 10 reproducing cells in both tumor and normal tissues. The radiation dosage regimen is generally defined in terms of radiation absorbed dose (rad), time and fractionation, and must be carefully defined by the oncologist. The amount of radiation a patient receives will depend on various consideration but the two most important considerations are the location of the tumor in relation to other critical structures or organs of the body, and the extent to which the tumor has spread. 15 Examples of radiotherapeutic agents are provided in, but not limited to, radiation therapy and is known in the art (Hellman, Principles of Radiation Therapy, Cancer, in Principles I and Practice of Oncology, 24875 (Devita et al.. 4th ed., vol 1, 1993). Recent advances in radiation therapy include three-dimensional con forma! external beam radiation, intensity modulated radiation therapy (1MRT), stereotactic radiosurgery and brachytherapy (interstitial radiation therapy), the 20 latter placing the source of radiation directly into the tumor as implanted "seeds". These newer treatment modalities deliver greater doses of radiation to the tumor, which accounts for their increased effectiveness when compared to standard external beam radiation therapy. Ionizing radiation with beta-emitting radionuclides is considered the most useful for radiotherapeutic applications because of the moderate linear energy transfer (LET) of the ionizing 25 particle (election) and its intermediate range (typically several millimeters in tissue). Gamma rays deliver dosage at lower levels over much greater distances. Alpha particles represent the other extreme, they deliver very high LET dosage, but have an extremely limited range and must, therefore, be in intimate contact with the cells of the tissue to be treated. In addition, alpha emitters are generally heavy metals, which limits the possible chemistry and presents undue 30 hazards from leakage of radionuclide from the area to be treated. Depending on the tumor to be treated all kinds of emitters are conceivable within the scope of the present invention. Furthermore, the present invention encompasses types of non-ionizing radiation like e.g. ultraviolet (LIY) radiation, high energy visible light, microwave radiation (hyperthermia therapy), infrared (IR) radiation and lasers. In a particular embodiment of the present invention UV 35 radiation is applied. 33 Received at IPONZ on 2 March 2012 The invention also includes pliarmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, Methods of using the compounds of the invention to prepare such compositions and medicaments are also described. Typically, the compounds of formula I used in the methods described are formulated by mixing at ambient temperature 5 at the appropriate pll, and at the desired degree of purity, with physiologically acceptable carriers, he,, carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pil of the formulation depends mainly on the particular use and the concentration of compound, but may range anywhere from about 3 i<> about 8, Formulation in an acetate buffer at pH 5 is a suitable embodiment. In an embodiment, the inhibitory compound for use herein is 10 sterile. The compound ordinarily will be stored as a solid composition, although lyophilized formulations or aqueous solutions are acceptable. The composition of tlie invention will be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include tie 15 particular disorder being treated, the particular mammal being treated, die clinical condition of tlie individual patient, the cause of the disorder, tlie site of delivery of the agent, the method of administration, tlie scheduling of administration, and other factors known to medical practitioners. The "effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit IAP interaction with caspases, 20 induce apoptosis or sensitize a malignant cell to an apoptotic signal Such amount is may he below die amount that is toxic to normal cells, or the mammal as a whole. Generally, the initial pharmaceutically effective amount of the compound of ihe invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg, for example 25 about 0,1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0,3 to 15 mg/kg/day. Oral unit dosage forms, such as tablets and capsules, may contain from about 25 to about 1000 mg of the compound of the invention, Tlie compound of the invention may be administered by any suitable means, including oral, topical, 30 transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. An example of a suitable oral dosage form is a tablet containing about 25mg, 50mg, lOOmg, 250mg, or 500mg of the compound of the invention compounded with about 90-30 mg anhydrous lactose, 34 WO 2008/07V7J5 PCT/ljS2»l»7/»8?532 about 5-40 mg sodium croscannellose, about 5-30mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An aerosol 5 formulation can be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution is typically filtered, e.g. using a 0.2 micron filter, to remove impurities and contaminants. 10 EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. Reagents and solvents were 15 obtained from commercial sources and used as received. Unjless otherwise noted, chromatographic purifications were performed using pre-packed silica gel columns on a CombiFlash Companion system by Teledyne-Isco, Inc. Lincoln, Nebraska. The identity and purity of compounds were checked by LCMS and 'H NMR analysis. 20 Abbreviations used herein are as follows: AcOH: acetic acid; . ACN: acetonitrile; Chg: cyclohexylglycine; DCM: dichloromethane 25 DIPEA: diisopropy lethy lam ine; DMAP: 4- dimethylaminopyridine; DME: 1,2-dimethoxy ethane; DMF: dimethylformamide; DM SO: dimethy Isul fox ide 30 EDC: 1 -ethy 1-3 -{3 -dimethy lam inopropy l)carbodi imide; EEDQ: 2-ethoxy-1 -ethoxycarbony 1-1,2-dihydroquinoline; EtOAc: ethylacetate EtOH: ethanol; LCMS; liquid chromatography mass spectrometry; 35 HATU: C)-(7-Azobenzotriazol-1 -yl)-1,1,3.3-tetramethyIuroniurn hexafluorophosphate; HOBt: N-Hydroxybenzoniazole 35 WO 2008/07V7J5 PCT/ljS2»l»7/l«?532 HBTU: 2-( 1 H-Benzotriazo 1- 1-yl)-1,1,3,3-Tetramethy 1 -uronium 11exafluorophosphale, HPLC: high performance liquid chromatography; Me OH: methanol; NHS: N-bromosttccinam ide; TASF: tris(d imethy lam in o)sn Ifoni um d i fi uorotri methy Is i I icate, TEA: ftiethylamine; TFA: trifluoroacetie acid; THF: tetrahy drofurart; 10 Example 2-[tert-Butoxycarbonyl-( 1H-pyrroI-2-yImethy l)-amino]-propionic acid O h2N^A NaCNBH OE! I % AcOH DMF N if' h | OEt di -tert-butyldi carbonate THF, H,0, NaHCO, IS 20 25 O^ nV* LiOH.HjO THF, H20 Boc d Soc a Alanine ethyl ester b (5g, 32.5mmol), pyrrole-2-carboxaldehyde a (3.1g, 32.5mmol), sodium cyanoborohydride (2.04g, 32,5mmol) and AcOH (1%) were mixed in DMF and stirred overnight, The reaction was quenched with PI A and DMF was evaporated, The mixture was diluted with EtOAc, washed by 0, IN NaOH, dried and concentrated to yield product c 2,5g, Trie resulting ester c (2.5g, 12,8mmol), di-tert-butyIdicarbonate (3.06g, 14mmol) were mixed in THF, H20 with NaHCOj and stirred overnight. THF was evaporated, and the mixiure was diluted with EtOAc, washed by IN NaOH, sat. NHjCl and brine. After dried, the mixture was concentrated to yield the Boc-proteeted ester d 3.3g. The Boc-protected ester d (1,67g, 5,6mol), lithium hydroxide mono hydrate (284tng, 6,77mmol) were mixed in THF and H;() at 0"C. THF was vacuumed ofl", and the solution was acidified by dilute H^SOc, extracted by EtOAc twice. Organic layers were combined, dried and evaporated giving product 2-[tert-butoxy carbony I-(1H-pyrrol-2-y Imethy 1}-amino]-propionic acid e, 30 36 WO 20II8/II7V7J5 PCT/ljS2»l»?/l«?532 Example 2 tetrahydropyranylglycine ,0, O Tetrahydropyranylgiycine was purchased from NovaBiochem, or synthesized according to the literature: Ghosh, A. K , Thompson, W. J.; holloway, M K., McKee, 5. P.; Duong, T. T.: Lee. H. 5 Y.: Munson, P. M.; Smith, A. M.; Wai, J, M, Darke, F. L.; Zugay, J. A.; Emini. E. A.; Schleife, W. A.; Huff, J. R : Anderson, P. S. J, Med Cham. 1993, 36, 2300-2310. Example 3 piper id inylgly cine Piperidinylglycinc was synthesized according to the procedures described by Shieh et al. ('Tetrahedron: Asymmetry, 2001, 12, 2421-2-125. 15 Example 4 4,4-diiuorocycIohexy {glycine O 4,4-difluorocyclohexyIglycine was made according to the procedures described in patent application US 20030216325. 20 Example 5 Bee (S)-2-amino-2-(4-hydroxycyclohexyl)acetic ac:d r i H N H2N m m "V0H 37 WO 2008/07V7J5 PC"T/L!S2(f07/087532 CkHN, C02Me 15 \ O . Q o n ^ OMe OMe CbzHN' "CO^Me i b c Following the procedure described by Slieih et al (Tetrahedron: Asymmetry, 2001, J2, 2421-2425), a solution of ketone a {8.4 g) and EtOAc (30 mL) was added to a solution of A'-Cbz-phosphonoglycine methyl ester b, TMQ {4,5 mL) and EtOAc {30 mL). The solution was 5 maintained at rt for 48h, then washed with IN HCl (3x50 mL), brine (1x50 mL) dried (Na2SOd), filtered, and concentrated. The residue was adsorbed onto Celite, and purified hy chromatography, then further purified by re-crystelizatioi? from EtOAc/hexanes to afford 5.2 g of product c. CbzHN ^C02Me CbzHN' "t02Me s d Following the procedure described by Sheih. (Tetrahedron: Asymmetry, 2001, 12, 2421-2425), a 10 solution of eneamide c (5.0 g), (S.S)-Mte-BPE-Rh(l) (1,5g, Strem Chemicals, New bury port, MA), and MeOH (100 mL) was shaken vigorously under ?0psi of H2 for 48h. The solvent was removed under reduced pressure. The residue was taken up in EtOAc, and filtered through Si02 with more EtOAc. The solvent was removed under reduced pressure to afford 4,0g of product d as a colorless solid, ~ /~A V0 x V V CbzHN'"' "C02Me BocHN^ To2M8 d e A mixture of Cbz-carbamate d, (4.0g) Boc20, (2.9g), 20% Pd(OH)2«C (1 .Og) and MeOH (30 mL) was maintained under an atmosphear of H2 for 6h, The mixture was filtered through Celite with MeOH. The solvent was removed under reduced pressure to afford 4.5 g of residue e, which was taken on directly. 38 WO 20118/11?<)735 PC'T/ U S 2 0117/1187S32 9 o BocHN" C "CO^Me SocHM ~CQ7Me f The residue e from above was dissolved in H20 (10 mL), AcOH (30 mL), THF (5 mL), and dichloroacetic acid (3 mL) and maintained at rt overnight. Water (5 mL) was added and the solution and maintaned until tiyroiysis was complete, as monitored by HPLC-MS, Solid Na2C03 5 was added cautiously until gas evolution ceased, the mixture was diluted with aq NaHCOj, and extracted with 10%BtOAc/DCM, The combined organic phases were washed once with brine, dried (Na2804), filtered, and concentrated. The residue was purified by chromatography to afford 2.9g of product f. 10 A mixture of ketone f (1,5g) MeOH (50 nil) was treated with NaBIM (290 mg) at 0 "C for 20 min. The mixture was acidifed to -pHI with I0%aq citric acid and the MeOH was removed under reduced pressure. The residue was diluted with water and extraced with 20%EtOAc/DCM. The combined organic phases were washed once with brine, dried (Na?SOj), filtered, and concentrated. The residue was purified by chromatography to afford I J7g of product g arid 0.23g IS of product h. A mixture of ester a (1.17g) Li0H-H20 (160mg), THF (3 mL) and water (4.5 mL) was stirred vigorously at rt overnight. The mixture was diluted with brine and exaustivly extraced with EtOAc. The combined organic phases were washed once with brine, dried (Ma2S04), filtered, and 20 concentrated to afford acid i (525mg). Example 6 N-Boc-N-cyclopropylmethy!■-L-alanine f f I S 39 WO 2008/07V7J5 PCT/ljS2»l»?/l«?532 0 o NaCNBH.-, H2N + H THP/l%AeOH MeOH O a £ di-£-Boc clicarbonatc NaHCOj THF. H20 Boc d o LiOH, H20 THF, H,0 ■OH i 5 L-alanine methyl ester hydrochloride a (5g, 3S,8mmol) and cyclopropanecarboxaldehyde b (2.67ml, 35.$mmol) were suspended in 50ml THF w/1% AcOH. Addition of 5nil of CHjOH made the cloudy solution turned to clear, NaCNBH4 (2.25g, 35.8mmol) was added and the reaction mixture stirred overnight. The reaction was quenched by addition of IN aq. NaOH, extracted by EtOAc twice, organic layers were dried over Na2SO< and concentrated to dryness. 10 The crude material was purified by chromatography using 30% EtOAc/hexane (stained by ninhydrin) to obtain the compound c (Ig, 18%). The compound c (lg, 6.37mmol) and di-t-boediearbonate (2.lg, 9.55mmol) were diluted in THF (20ml) and H20 (20ml), NaHCO;, (1,3g, 15,9mmol) was added. The reaction mixture stirred overnight for completion. THF was removed under reduced pressure, and the aqueous layer was extracted by EtOAc 3 times. 15 Combined organic layers were washed by IN NaOH, sat, NIT;C1 followed by brine, the concentrated to dryness. The Roc-protected compound d (l,39g, 5.40mmol) was stirred with LiOH.HjO (1.14g, 27mmol) in THF (20mI) and 1-I20 (20ml) overnight at room temperature. THF was stripped off, and the aqueous layer was adjusted to pH=4 by adding 10% citric acid, then extracted by EtOAc 3 times. Combined organic layers were washed by brine and 20 concentrated. The crude was purified by reverse phase C-I8 column eluted by 0%-50% aeetonitrile/HjO to give pure compound e as a white solid (794mg). 40 WO 20tl8/«?V7J5 PCT/ljS2»l»?/l«?532 Example 7 N-Boc-N-methyl-L-alariine-L-cydohexy{glycine BocN NH COCK A solution of Fmoc-L-cy clohexy(glycine (3.6 g. 9.6 mmol) dissolved in DCM (50 mL) and DIPEA (5,6 mL, 32 mmol) was added to 2-chlorotrityl chloride resin (5 g, 8 mmol) and gently 5 agitated for 3 hours at room temperature. The resin was washed with DCM 4 times, DCM/MeOH/DIPEA (17:2: t) 3 times, DCM 3 times, and 2 times dimethylacetamide (DMA). The Fmoc group was removed by treating the resin with 20% pi peri dine/DMA (50 mL) for 15 minutes. The resin was washed with DMA 6 times, A solution of Boc-N-methy(alanine (3.3 g, 16 mmol), HBTU (6.1 g, 16 mmol), and DIPEA (5.6 mL, 32 mmol) and DMA/DCM (1: 1, 50 mL) 10 was added to the resin and gently agitated for 2 hours at room temperature. The resin was washed with DMA 5 times, DCM 2 times, and dried under reduced pressure. The dipeptide was cleaved from the resin by gentle agitation with HOAc/TFE/DCM (1:1:3, ;00 mL) for 2 hours at room temperature. The resin was removed by filtration and the solution concentrated. Residual AcOH was removed by azeotroping with hexanes (15 times volume). The solid residue was purified by 15 reverse-phase H'PLC (Cl8, MeCN-H20, 0. !%TPA) and the solvents removed by lyophyiization to provide 1.2 g (43%) of dipeptide N-Boc-N-methy I-L-alanine-L-cyclohexy lglycine as a white powder. 20 Example 8 N -Boc-N-methy i-L-a I an i rte- L-dehy dropy rany Igly ci ne A mixture of N-Cbz-dehy dropy rany Igly cine methyl ester a (Burk, M, j,; Gross, M. F,; Martinez, J. P, J. Am Chem, Soc 1995, //?, 9375, and references therein) (5.2 g, 1? mmol), 5% Pd-C (500 mg), MeOH (75 mL) and THF (25 mL) was maintained under an atmosphere of 112 for 24 h. The 25 mixture was filtered through Celite and the Celite washed with MeOH, and concentrated under reduced pressure to afford a quantitative yield of amine b as a colon less oil, which was carried on directly. O" C02Me H,N~ XOzMe ' D i 41 WO 2008/07V7J5 PCT/ljS2»l»?/l«?532 10 20 N' XOzMe b ' 5 The amine b prepared above was combined with CH2CI2 (40 mL), saturated aqueous NaHC03 (40 mL) and cooled to 0 °C. Benzy loxy carbony I chloride (3.0 ml.,) was then added dropwise and the mixture stirred vigorously overnight. The phases were separated and the aqueous phase extracted with CHjC12 (3 x 20 mL), The combined organic phases were washed with brine (1 x 50 mL), dried (NaaSO^), filtered, adsorbed onto Celite and chromatographed (1SCO, 120 g silica column, gradient elutton 5-55% EtOAc-hexanes) to afford 4.15 g (80%) of racemic Cbz-py ranyIglycine methyl ester. The enantiomers were separated on a Chiracel OD column eluting with 10% EtOH-hexanes, The desired S-enantiomer c elutes first under these conditions. I s GOoMc? H2N" "GOgMe d A mixture of (S)-/V-Cbz-pyranyl glycine c methyl ester (2.4 g, 7.82 mmol) 10% Pd-C (700 mg), MeOH (80 mL) was maintained under I atmosphere of fL for 24. h. The mixture was filtered through Celite with MeOH, and concentrated under reduced pressure to afford 1.35 g (100%) of 15 amine d as a colorless oil. Alternatively, pyranyl glycine can be synthesized in enantiopure form following the procedure of Ghosh (Ghosh, A. K.; Thompson, W, J.; Hoiloway, M K.; McKee, S. P.; Duong, T, T.; Lee, H, Y.; Munson, P. M,; Smith, A, M.; Wat, J. M.; Darke, P, L,; Zugay, J. A,; fmini, E. A.; Schleif, W. A.; Huff, J. R,; Anderson, P. S. J, Med. Chem., 1993, 36, 2300). O BocN^X. BocN^^N^COaMe " "OH — - I ? H2N C02Me i t f A mixture of amine d (1.35 g, 7.8 mmol), iV-Boc-/V-niethyl alanine e (1.74 g, 8.6 mmol), EDC (1.65 g 8.8 mmol) and MeCN {50 mL) was maintained at rt overnight. The MeCN was removed under reduced pressure, and the residue diluted with EtOAc, washed with 0.5 N HCl (3x10 mL), 42 WO 20tl8/l»7t>735 PCT/ljS2»l»?/l«?532 0.5 N NaOH (3 x 10 mL). dried (MgS04). filtered, and concentrated to provide 2,1 g (75%) of protected dipeptide f, as a clear oil. To a 0 °C solution of ester f (2 JO g, 5.86 mmol) and THF (50 mL) were added Li01MI20 (1,23 g, 29,3 mmol) and water (2 mL). The mixture was maintained at 0 °C for 2 h, then the cooling bath was removed and the mixture was stirred overnight, Most of the THF was then removed under reduced pressure and the residue was diluted with CH2C12, washed with 0,5 N HCl, dried (MgSOi,), filtered, and concentrated to provide 1,53 g (78%) of dipeptide M-Boc-N-methyl-L-a I an ine- L-delty dropy rany I gly c ine g, as a colorless solid, Example 9 N-Boc-protected cyclic sulfonyl amino acid Sulfide g (810 mg, 2.5 mmol), synthesized according to the general procedure of Shieh [Shieh, W-C.; Xue, S.; Reel, N,; Wu, R , fitt, J.; Repic, O, Tetrahedron: Asymmetry. 2001, 12, 2421 -2425], was dissolved in methanol (25 mL). Oxone (4.5g) was dissolved in deion.ized water (25 mL), The methanol solution of substrate was cooled to-10 °C, and the aqueous solution of oxone 20 was added to the reaction slowly. The reaction was kept on ice and gradually allowed to wanm to room temperature while stirring overnight. Deionized water was used to dilute the reaction to approximately 150 mL, then poured into 90% ethyl acetate-hexanes for extraction. The organic phase was dried (Na2S04), adsorbed onto Celite and purified by chromatography 1SCO CombiFlash 40 g column, 5-90% ethyl acetate-hexanes over 30 mm to afford 804 mg (2.27 mmol, 25 91 %) of the product su I fone b. 43 WO 20II8/II7V7J5 PCT/ljS2UII?/l«?532 Following the general procedure of Burk [Burk, M. j.; Gross, M, P.; Martinez, J. P. J. Am. Chan. Soc. 1995, 117, 9375 9376.], alkene b (774 mg 2.19 mmol), dry methanol (40 mL), and [(S,S> 5 Me-BPE-Rh(COD)J+OTf (500 mg, 0.8 mmol) were mixed in a Pair shaker flask purged with nitrogen, Tlie Parr flask was evacuated and subsequently charged to 60 psi with hydrogen gas and shaken vigorously overnight. Methanol was removed under reduced pressure, and crude product was filtered through a small plug of silica gel using ethyl acetate. Evaporation of the solvent yielded 730 mg (2.0 mmol, 94%) of product c with >98% yield. 10 Z-protected amino ester c (804 mg, 2.27 mmol) was dissolved in methanol (16 mL). To this solution was added BOC-anhydride (1.5 g, 6.8 mmol), followed by 20% Pd(OH)aC (250 mg). 15 AH air was removed from the reaction flask by house vacuum, and ihe mixture was stirred vigorously for 5 min. Tlie flask was then filled with hydrogen gas and allowed to stir vigorously at room temperature for 6 h, After evacuating the hydrogen atmosphere, the mixture was filtered through Celite using methanol, and crude product d was obtained by evaporation of the solvent (508 mg, 1.56 mmol, 70% yield). Ester d (508 mg, 1,56 mmol) was dissolved in 8 mL of THF. De ionized water (4 mL) was added, followed by LiOH - H2Q (120 mg, 2.8 mmol), The mixture was stirred at room temperature 44 WO 2008/07V7J5 PCT/ljS2»l»?/»8?532 overnight, acidified using aqueous I N HCl and extracted into ethyl acetate (3 X 25 mL). The organic extracts were dried further with NaiSO*, filtered and concentrated to give 372 mg (1.21 mmol. 78% yield) of the N-Boc-protccted cyclic sulfonyl amino acid e, which was carried on without purification. Example 10 N -Boc-N -methy 1-L-gtyc i ne H 9 ^^1 ^ O - • v°y" ' ' O ' \ 6 OH a b Following the general procedure of Grieg fBlaney, P.; Grigg, R.; Rankovic, Z.; Thorn ton-Pett, 10 ML; Xu, J, Tetrahedron, 2002, 5S, 1719-1737] a roundbottoiu flask was charged with sodium hydride (480mg 60% dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogen for IS min. THF (6.0mL) was added to the flask, and the suspension was cooled to 0 "C using an ice water bath. A separate flask was charged with BOC-glyeine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide (1.0 mL, 12 mmoL 4 equiv). This mixture was added dropwise to the Nail 15 suspension in THF, with vigorous stirring at 0 °C. After 1 h of stirring, the reaction was warmed to room temperature and allowed to stir overnight. Tlie reaction was again cooled to 0 °C, and' methanol (4 mL) was added very slowly to quench the excess hydride. Deionized water was added to dilute the mixture, and methanol was removed under reduced pressure. Impurities were extracted into 90% ethyl acetate-hexanes, the aqueous layer was then acidified by adding solid 20 citric acid until the pH reached 2-3. The product was extracted into 90% ethy! acetate-hexanes. This organic layer was dried (Na;S04) and filtered. Removal of the solvents under reduced pressure afforded a quantitative yield of the product b. 25 Example 11 N-Boc- fluoro- L-al an ine H2NY^°H + X0A0A0X f ® b c A mixture of unprotected amino acid a (775 mg, 7.24 mmol) and sodium carbonate (1.69 g, 16.0 mmol) was dissolved in a 1; 1. solution of deionized water and THF (15 mL each). To this mixture 30 was added BOC-anhydride b (1.73 g, 7.96 mmol). The mixture was stirred at room temperature overnight, and THF was removed under reduced pressure. The mixture was then acidified to pH 2-3 with saturated aqueous citric acid, and product was extracted into 10% ethyl acetate- 45 WO 2008/07V7J5 PCT/ljS2»l»?/l«?532 dichloromethane. The organic layer was dried (Na2S04), filtered and concentrated under reduced pressure to afford clean BOC-protected amino acid c (1.40 g, 6,7 nunol, 93%) to be used without further purification. 5 Example 12 compound 1 ♦ 6'- In a 100 mL round-bottomed flask, compound a (1,62 g, «.97 mmol) and 2-aniino-S-bromopyridine b (1,0 g, 6.00 mmol) were mixed together in ethanol (50 mL) and stirred at 80°C I© for 48h. The mixture was then cooled down and concentrated. The residue was adsorbed on silica gel and purified by Rash chromatography (f 00% DCM to 10% Methanol/DCM) to afford 881 mg (35.4%) of compound c as an orange oil. LCMS: M/2 = 401. 15 Into a 25 mL round-bottomed flask, compound c (150 mg, 0.37 mmol), pheny I boron ic acid (68 mg. 0.56 mmol), tetrakis(tripheny iphosphine)palladium(0) (30 mg, 0,03 mmol) and potassium carbonate (78 mg, 0.56 mmol) were mixed together in DMF (2,0 nil,). The mixture was stirred at 100°C under nitrogen atmosphere for I8h. The mixture was then cooled down, diluted with ethyl acetate (30 mL) and washed with water (50 mL). The aqueous phase was extracted with ethyl 20 acetate (30 mL). The combined organic phases were washed with saturated aqueous NaHCOj (50 mL) and brine (50 mL), dried with MgS04, filtered and concentrated. The residue was adsorbed on silica gel and purified by flash chromatography (30% ethyl acetate/hexane to 100% ethyl acetate) to afford 126 mg (84%) of com pound d as a pale yellow oil LCMS: MJZ = 398. 25 46 WO 20II8/II7V7J5 PCT/ljS2»l»?/l«?532 Hk 10%Pd/C EtOH HI e 10 15 In a 50 ml. round-bottomed flask, compound d (120 mg, 0.30 mmol) was dissolved in ethanol (10 mL) and 10% palladium on carbon (24 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 48 h. The mixture was risen filtered over celite and washed with ethanol The filtrate was concentrated to afford 78 tug (98%) of compound e as a pale yellow oil, LCSM: Mil, - 264, In a 10 mL round-bottomed flask, compound e (78 mg, 0,30 mmol), compound f (120 mg, 0,36 mmol), N.N-diisopropylcarbodiimide (0,074 mL, 0.47 mmol) and l-hydroxy-7-azabenzotriazole (64 mg, 0.47 mmol) were mixed together in dichloromethane (2,0 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 5h, The mixture was then concentrated on silica gel and purified by flash chromatography (100% DCM to 7% MeOH/DCM) to afford 182 mg (50%) of compound g as pale yellow oil. LCMS: Mil. - 590, In a 25 mL round-bottomed flask, compound g (192 mg, 0,33 mmol) was dissolved in a solution of 4N hydrogen chloride in dioxane (4 mL, 30 mmol), The mixture was stirred at room temperature for lh, The mixture was then concentrated and the residue was purified by HPLC to afford 13.3 mg (8.3%) of compound I as a white solid. LCMS: M/2 = 490, O •O 47 WO 2008/07V7J5 PCT/ljS2»l»7/l«?532 Example 13 (S>- benzy 1-2-(2-bromoacety I)py rro I id ine-1 -carboxy late cbz^ Alpha broino ketone was prepared according to the general procedure of Bures and Kulhanek ('Tetrahedron: Assymetry (2005) 16(7): 1347-1354.) A solution of Diazald (4.9991 g, 23.3 mmol), sodium sulfate (20.14 g). and diethyl ether (15 mL) was stirred for 15 min. The resulting mixture was then filtered and added dropwise to a solution of potassium hydroxide (5.0050 g) in water (S mL) and ethanol (10 mL) at 65°C in a mini Diazald apparatus and distilled until the reaction mixture was pale yellow. The distilled diazomethane 10 solution was stored over sodium hydroxide pellets at 4°C. To a solution of Cbz-Pro-OH (2.9986 g, 12 f) mmol) in dry tetrahydrofnran {40 ml,) and dry diethyl ether (40 mL) was added triethylaniine (1.7 mL, 12.2 mmol). The solution was cooled to -25°C and isobutyl chlorofonnate (1.6 mL, 12.3 mmol) was added dropwise. The resulting 15 solution was stirred at --250C for 30 min before wanning to 10°C. The diazomethane solution was added to the reaction mixture. The sample was stirred at 10°C for 1 hour. The reaction mixture was concentrated to one half of its original volume and washed once with saturated sodium bicarbonate (50 mL). The organic layer was dried over magnesium sulfate and filtered. The etude material was adsorbed onto silica gel and purified by flash chromatography (40 g SiO?, 20 0-50% ethyl acetate in hexanes) to give the diazoketone (2.29 g, 8.3 mmol, 69%). The diazoketone (1.72 g, 6.3 mmol) was dissolved in acetic acid (40 inL) and cooled to 0°C. 48% HBr (LI mL, 9.7 mmol) was added dropwise to the solution. The reaction mixture was wanned to room temperature and stirred for 1 hour. The sample was poured into ice and added sodium 25 bicarbonate (5 g). The solution was extracted with dichloromethane (3 x 100 mL). The organic extracts were washed with saturated sodium bicarbonate (3 X 100 mL). The dichloromethane extracts were dried over magnesium sulfate, filtered, and concentrated to give the a-bromoketone (S)- benzy L2-(2- bromoacely I)py rrol id ine-1 -carboxy late (1.771 g, 5.4 mmol, 86%). The a-bromoketone was unstable at room temperature as well as 4QC when stored neat. 5 30 48 WO 20118/1179735 PC'T/|jS2(HI7/»87532 Example 14 (S)-benzvI 2-(8-phenylimidazo[L2-a]pvridin-2-yr)pvrrolidine-l-carboxvlate o € I N ^V-Br J (S)-benzyl-2-(2-bromoacetyl)pyrrolidine-l -carboxylate (I 771 g, 5.4 mmol), 2-amino-3-bromo- pyridine (0,9412 g, 5.4 mmol), and ethanol {20 mL) were combined under nitrogen. The reaction 5 mixture was heated to 78°C and stirred overnight. The sample was concentrated and saturated sodium bicarbonate {50 ml.) was added. The mixture was extracted with ethyl acetate (3 x 50 mL). The ethyl acetate extracts were dried over magnesium sulfate and filtered. The crude material was adsorbed onto silica gel and purified by flash chromatography (40 g Si02, 0-100% ethyl acetate in hexanes) to give (S)-benzyL2-(8-br0?n0tniidazo[ 1,2-a]pyridin-2-yI)pyrrolidine-l -10 carboxy late (0.869 g. 8.3 mmol, 2.2 mmol, 40%). To a 2-5 ml microwave vial with a stirbar was added (S)-betszy 1-2-(8-bromoimidazo[1,2-aJpyridin-2-y l)pyrrolidine-1 -carboxy )ate (0.258 g, 0.644 mmol), phenytboronic acid (0.1026 g, 0.8415 mmol) and potassium carbonate (0.142 g, 1.03 mmol). The reaction vial was evacuated i and purged with N2 three times. Tetrak is(tri pheny I phosph ine)-pa! ladium{0) (0.0395 g, 0.0342 mmol) was then added and She vial evacuated and purged with Is^five times. 3 ml of DMF was added, then 1 ml of deoxygenated H>0, and the vial was microwaved at 130°C for 40 min. LC/MS showed no starting material remaining, so the reaction was poured into 200 ml H20 and extracted with ethyl acetate (3x 50 ml) and the combined extracts were dried with MgSOo, filtered 20 and concentrated under reduced pressure. The crude material was dissolved in dichloromethane arid applied to a 12g column which had been equilibrated in hexanes. The material was flashed using a gradient of 0% to 50% ethyl acetate iri hexanes. The product containing fractions were combined and evaporated under reduced pressure to give the desired imidazopyridine (S)-benzy I 2-(8-pheny limidazof 1,2-a}py ridin-2-yl)pyrrolidine-1 -carboxy late . 49 WO 20H8/07V735 PCT/HJS2007/087532 Example 15 (2S)-benzyl 2-(8-o-toiyiimidazo[! ,2-a]py rid i n-2-y ] )py rro I idine-1 -carboxy late Following procedures of example 14, (S)-ber!zyt-2-{8-bromoimida2o[ 1,2-a]pyridin-2-yl)pyrrolidine-1 -carboxyjate (0,250 g, 0.62 mmol), o-tolyi boronic acid (0.1101 g, 0.81 mmol), 5 potassium carbonate (0.1292 g, 0.93 mmol), and tetrakis(tri pheny Iphosphtne)palladiuni(O) (0.0360 g, 0.03 mmol) were reacted to give crude (2S)-benzyl 2-(8-o-toIylimidazo[ 1,2-aJpyridm- 2-y I)py rrol id ine-1 -carboxy I ate. The crude material was adsorbed onto silica gel and purified by flash chromatography (4g Si02, 0-70% ethyl acerate in hexanes) to give the final product (0.247 g, 0.60 mmol, 74%), 10 Example 16 (2S)-benzy l-2-(8-(2-(tri fluoromethy I )pheny 1 )im idazo[ 1,2-a]pyridin-2-y IJpyrrol id ine-1 -carboxy late IS following procedures of example 14. (S)-benzyI-2-(8-bromoimidazo[l,2-a]pyriditi-2-yl)pyrrolidine-l -carboxy late (0,250 g, 0.62 mmol), 2-tri fluoromethy Iphenyl boron ic acid (0.1538 g, 0.81 mmol), potassium carbonate (0.1292 g, 0,93 mmol), and tetrak is(tripheny lphosph me)pa I tad i um(0) (0.0360 g, 0.03 mmol) produced the crude material which was adsorbed onto silica gel and purified by flash chromatography (4g Si02, 0-100% ethyl 20 acetate in hexanes) to give (2S)-benzyl-2-{8-{2-(trifluoromethy 1 )pbenyl)i m i da zo [ 1,2-a]pyridin-2-yl)pyrrolidine-1 -carboxy[ate (0.264 g, 0.57 mmol, 70%). 50 WO 2OtlS/ll7V735 PCT/US2007/087532 Example 17 (2S)-benzy 1-2 -(8-(2-methoxv pheny l)im i dazo [ 1,2-a] pyr idin-2-y 1 )py rro I id ine-1 - Following the procedures of example 14, (S)-benzyl-2-(8-bromoimidazo[ 1,2-a]pyridin-2-5 y l)pyrrol id ine-1-carboxy late (0250 g, 0.62 mmol), 2-methoxy phenyl boron ic acid (0.1231 g, 0,81 mmol), potassium carbonate (0,1292 g, 0.93 mmol), and letrakisftripheny 1 phosphine)- palladium(O) (0.0360 g, 0,03 mmol) produced the crude material which was adsorbed onto silica gel and purified by flash chromatography (4g Si02, 0-100% ethyl acetate in hexanes) to give (2S)-benzy l-2-(8-(2-methoxypheny l)iin idazo[ i ,2-alpy rtdin-2-y i)py itoI id ine-1 -carboxy late (0.269 g, 10 0,63 mmol, 78%). Example 18 (2S)- ben zy l-2-(8-(naph thalen- l-yl)imidazo[l ,2-a]pyri din-2-yl)py rrol idine-1 - Following the procedures of example 14, (S)-benzy l-2-(8-bromoimidazo[ 1,2-a]pyridin-2- yOpyrrolidine-1-carboxylate (0.250 g, 0.62 mmol), l-napthy! boronic acid (0,1405 g, 0,82 mmol), potassium carbonate (0.1340 g, 0.97 mmol), and tetrakis(triph eny lphosph inc)palladium(0) (0.0430 g, 0.04 mmol) produced the erode material which was adsorbed onto silica gel and 20 purified by flash chromatography (4g Si03, 0-50% ethyl acetate in hexanes) to give (2S)-benzyl 2-(8-(naph th alen-1-y l)im ida?x>[ 1,2-a Ipy rid tn-2-y I )py rrol idine-1-carboxy late (0.183 g, 0,41 mmol, 66%). carboxy late carboxyl ate 51 WO 20II8/II7V7J5 PCT/US2007/087532 Example 19 (2S)-benzyl-2-(8 -(2-fl uoropheny 1) im i dazo[ 1,2-a]pyridin -2-y l)py rrol i dine-1 -carboxy late Following the procedures of example 14, (S)- hen zy 1 -2-( 8- hromoi m i dazo[ 1,2- a]py rid in -2-yi)pyrrolidine-1 -carboxylate (0.2489 g, 0,62 mmol), 2-fluoropheny! boronic acid (0.1217 g, 0.87 mmol), potassium carbonate (0.1449 g, 1.05 mmol), and tetra ki s(tripheny lphosphine)-pailadium(O) (0.0532 g, 0.05 mmol) produced the crude material which was adsorbed onto silica gel and purified by flash diromatography (4g SiO>, 0-60% ethyl acetate in hexanes) to give (2S)-benzyl 2-(8-(2-fluoropheny})imidazof 1,2-a}pyridin-2-y!)pyrro]idine-1 -carboxylate (0.62 mmol, 100%), Example 20 (S)-benzy I -2-( 6- methy!- 8-p heny I im idazo[ 1,2-a]py ridin -2-y I)pyno I idine-1 - carboxy I ate Following the procedures of example 14, (S)-benzyl-2-(2-bromoacety ()py rrol idine- 1-carboxylate (0.295 g, 0,90 mmol) and 2-amino-3-bromo-5-methy{pyridine (0,1765 g, 0,94mmol), produced the crude material which was adsorbed onto silica gel and purified by flash chromatography (12g Si02, 0-50% ethyl acetate in hexanes) to give (S)-benzyl-2-(8-bromo-6-methylimidazof1,2-a]pyr id in-2-yl)py rrol idine-1 -carboxy late (0.165g, 0,40 rnmol, 44%). (S)- ben zy I -2-(8-bro mo-6-m ethy I imidazo[ 1 ,2 -a]py ridi n-2-y l)py rrol idine-1 -carboxy late (0.165g, 0.40 mmol), phenyl boronic acid (0.0740 g, 0.61 mmol), potassium carbonate (0,1449 g, 0.65 mmol), and tetrakis(triphenyIphosphine)palladium(0) (0.0351 g, 0,03 mmol) produced the crude material which was adsorbed onto silica gel and purified by flash chromatography (4g Si02, 0-50% ethyl acetate in hexanes) to give (S)- benzy i -2-(6-methy I -8-pheny I im idaxo [ 1,2-a]pyridin-2-yl)pyrrolidirte-1 -carboxylate (0.40 mmol, 100%). Ct 52 WO 20118/117V735 PCT/US2007/087532 Example 21 (S)-benzyl-2-(7-methy l-8-pheny 1 irnidazof 1,2-a]pyridin-2-y l)py rrolid ine-1 - carboxylate 5 Cbz' C hi following the procedures of example 14, (S)-benzyl-2-(2-bromoacetyl)pyrrolidi!ie-l-carboxylate (0.400 g, 1.23 mmol) and 2-amino-3-bromo-4~metbylpyridine (0.2344g, 1.25 mmol), produced the crude material which was adsorbed onto silica gel and purified by flash chromatography (12g SiOj, 0-50% ethyl acetate in hexanes) to give (S)-benzyl-2-(S-bromo-7-methylimidazo[ 1,2-10 ajpyridin-2-y l)py rrolidine-1 -carboxylate (0.239g, 0.58 mmol, 47%). (S)-bettzyl 2-(8-bromo-7-methy I im i dazo [1,2 -ajpyridi t: -2-y l)py rro I id i n e-1 -carboxy late (0.239 g, 0.58 mmol), phenyl boronic acid (0,0936 g, 0,77 mmol), potassium carbonate (0,1496 g, 1.08 mmol), and tetrakis(triphenytphosphine)palladium(O) (0,0534 g, 0.05 mniol) produced the crude 15 material which was adsorbed onto silica gel and purified by flash chromatography (4g Si02, 0-60% ethyl acetate in hexanes) to give (S)-benzyl 2-(7-methy I-8-pheny Itmi dazo [ 1,2-a]pyridin-2-yl)pyrrolidine-1 -carboxylate (0.58 mmol, 100%), 20 Example 22 IAP inhibition assays In the following experiments was used a chimeric BIR domain referred to as MLXB1R3SG in which II of 110 residues correspond to those found in XIAP-BIR3, while the remainder correspond to ML-IAP-BIR, The chimeric protein MLXBIR3SG was shown to bind and inhibit 25 easpase-9 significantly better than either of the native BIR. domains, but bound Smac-based peptides and mature Smac with affinities similar to those of native ML-IAP-BIR, The improved caspase-9 inhibition of the chimeric BIR domain MLXBIR3SG has been correlated with increased inhibition of doxorubicin-induced apoptosis when transfected into MCF7 cells. 53 WO 2008/07V7J5 PCT/ljS2»l»?/l«?532 MLXBIR3SG sequence: MGSSHHHHHHSSGLVPRGSHMLETEEEEEEGAGATLSRGPAFPGMGSEELRLASFYDW PLTAEVPPELL A A AG FFHT GHQDKVRCFFC YG G LQS WKRG DDP WTEH A K WPPG CQFLL RSKGQEYINNIHLTHSL (SEQ ID NO.: I) 5 TR-PRET Peptide Binding Assay Time-Resolved Fluorescence Resonance Energy Transfer competition experiments are performed 10 on the Wallac Victor! Multilabeled Counter Reader (Perkin Elmer Life and Analytical Sciences, Inc.) according to the procedures of Kolb et al (Journal of Bio molecular Screening, 1996, I(4):203 ). A reagent cocktail containing 300 nM his-tagged MLXBIR3SG; 200 nM biotinylated SMAC peptide (AVPI); 5 pg/mL anti-lils allophycocyanin (XL665) (CISBio International); and 200 ng/mL streptavidin-europium (Perkin Elmer) was prepared in reagent buffer (50 niM Tris [pH 15 7.21, 120 mVf NaCI, 0.1% bovine globulins, 5mM D1T and 0.05% octylgkicoside). (Alternatively, this cocktail can be made using europium-labeled anti-His (Perkin Elmer) and strepta v id in -all ophycocyan i n (Perkin Elmer) at concentrations of 6.5 nM and 25nM, respectively). The reagent cocktail is incubated at room temperature for 30 minutes. After incubation, the cocktail is added to 1:3 serial dilutions of an antagonist compound (starting 20 concentration of 50 pM) in 384-well black F1A plates (Greiner Bio-One, Inc.). After a 90 minute incubation at room temperature, the fluorescence is read with filters for the excitation of europium (340 nrn) and for the emission wavelengths of europium (615 nm) and a allophycocyanin (665 nm). Antagonist data is calculated as a ratio of the emission signal of allophycocyanin at 665 nrn to that of the emission of europium at 615 nm (these ratios are multiplied by a factor of 10,000 for 25 ease of data manipulation). The resulting values are plotted as a function of antagonist concentration and fit to a 4-parameter equation using Kaleidograph software (Synergy Software, Reading, PA). Indications of antagonist potency are determined from the lCsa values. Polarization experiments were performed on an Analyst HT 96-384 (Molecular Devices Corp.) according to the procedure of Keating, S.M., Marsters, J, Beresini, M.> Ladner, C., Zioncheck, K., Clark, K., Arellano, F.. and Bodary., S.(20O0) in Proceedings of SPIE : In Vitro Diagnostic Instrumentation (Colin, G.E., Ed.) pp 128-137, BeUingham, WA, Samples for fluorescence 35 polarization affinity measurements were prepared by addition of 1:2 serial dilutions starting at a final concentration of 5uM of MLXBIR3SG in polarization buffer (50 mM Tris [pH 7.2], 120 54 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> Received at IPONZ on 2 March 2012 mM X;tCI, r'o bm-im.- globulins 5mM PTT and 0.05% octylglitcosidc) to 5-cuiboxyllouresedn- coujusatct) AVPdi-Phe-Nlf; {AYP-dtPhe-F'AM) at 5 nM final concentration. OH .. I "( X " Q O O [I / HN' \\ O - •< /f o .--X r O •O "OH -NH NHy o AVP~diPhe~l'AM probe i lit- reactions were read alter an nicoixnion lime of 10 minutes at room tempera I ure with siandard cut-off fillers lor die fluorescein fluorophore = 4X5 nm; a,.„ 530 rtmj in 96-well black HE% plates {Molecular Devices Corp.). Fluorescence values were plotted as a function of the 10 protein concents ation. and die IC50s were obtained by titling the data to a 4-parameter equation using Kalcidograph software (Synergy software, Reading, PA). Compel it ion experiments were performed by addition of the M1.XBIR3SG at 30 nM to wells containing 5 nM of (he AVP-diPhe-FAM probe as well as 1.3 serial dilutions of antagonist compounds starling at a concentration of 30') u'vl in The polarization buffer. Samples were read after a 10-mioute incubation. Fluorescence 15 polarization values were plotted as a function of the antagonist concentration, and tlie IC5,i values were obtained b\ fining the data to a 4-parameter equation using Kalcidograph software (Synergy software, Reading. PA). Inhibition constants (K,) for the antagonists were determined from the ICsn \alues. Compounds of the invention that were tested in this assay exhibited a K.i or less than 50uM. For example, compound 7 had a Ki of 18.917, compound 20 had a Ki of 1.8312, 20 compound 1 had an Ki of 0.0891 and compound 8 had a Ki of 2.3067. In tins specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing tlie features of die invention. Unless specifically stated otherwise, reference to such externa! documents is not to be construed as an admission that such documents, or such sources of 25 information, m any jurisdiction, are prior art, or form part of the common general knowledge in the art. 55 Received at IPONZ on 27 February 2012 What we claim is:

1. A compound of formula (I): zkjr~ Q wherein X: and X2 are each independently O or S; Y is CT!2; Z is H, alkyl, a carbocycle or a heteroeyele; wherein said alkyl, carbocycle and heteroeyele is optionally substituted with one or more hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, optionally substituted alkyl, amino, cyano, nitro, amidino, guanidino, an optionally substituted carbocycle or an optionally substituted heteroeyele; and wherein one or more CI I2 or CH groups of an alkyl is optionally replaced with -0-, -S-, -S(O)-, S(0)2, -N(Rg)-, -C(O)-, -C(0)-NR8-, -NR8-C(0)-, -SO:-NRs-. -NRx-SO;-, -NRs-C(())-NRs-. -NR8-C(NH)-NR8-, -NR8-C(NH)-, -C(0)-0- or -O-C(O)-; Q is H, halogen, hydroxyl, carboxyl, amino, nitro, cyano, alkyl, a carbocycle or a heteroeyele; wherein said alkyl, carbocycle and heteroeyele is optionally substituted with one or more hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, optionally substituted alkyl, amino, cyano, nitro, amidino, guanidino, an optionally substituted carbocycle or an optionally substituted heteroeyele; and wherein one or more CI 12 or CH groups of an alkyl is optionally replaced with -0-. -S-. -S(0)-. S(0)2, -N(R8)-, -C(0)-. -C(0)-NR8-, -NR8-C(0)-, -S02-NR8-, -NR8-S02-, -NR8-C(0)-NR8-, -NR8-C(NH)-NR8-, -NRs-C(NH)-, -C( 0)-0- or -O-C(O)-; R; is H; R2 is morpholino or cyciohexyl; R ; is methyl; 56 Received at IPONZ on 27 February 2012 R3' is H; r t is methyl; R4' is II; R5 is TI; r„ and R(,' are each H; R- is J i. cyano, hydroxyl, mercapto, halogen, nitro, carboxyl, amidino, guanidino, alkyl, a carbocycle, a heteroeyele or -U-V; wherein U is -0-, -S-, -S(O)-, S(0)2, -N(R8)-, -C(O)-, -C(O)-NRg-, -NRg-C(O)-, -S02-NR8-, -NR8-S02-, -NR8-C(0)-NR8-, -NR8-C(NTI)-NR8-, -NR8-C(NII)-, -€'(())-()- or -()-("(())- and V is alkyl, a carbocycle or a heteroeyele; and wherein one or more ( '11;> or CH groups of an alkyl is optionally replaced with -0-, -S-, -S(O)-, S(0)2, -N(Rg)-, -C(O)-, -C(0)-NRg-, -NRg-C(O)-, -SO-NR*-. -NRx-S02-. -NR8-C(0)-NR8-, -C(0)-0- or -O-C(O)-; and an alkyl, carbocycle and heteroeyele is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano nitro, amidino, guanidino, an optionally substituted carbocycle or an optionally substituted heteroeyele; Rg is H, alkyl, a carbocycle or a heteroeyele wherein one or more CII2 or CH groups of said alkyl is optionally replaced with -0-, -S-, -S(O)-, S(0)2, or -C(O)-; and said alkyl, carbocycle and heteroeyele is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mcrcapto, oxo (=0), carboxyl, acyl, halo-substituted alkyl, amino, cyano nitro, amidino, guanidino, an optionally substituted carbocycle or an optionally substituted heteroeyele; and m is 0 to 4; wherein, for each occurrence, alkyl is independently a branched or unbranched, saturated or unsaturated aliphatic hydrocarbon; or a salt or stereoisomer thereof.

2. The compound of claim 1, wherein Z is II, halogen or alkyl.

3. The compound of claim 1, or claim 2, wherein Q is a carbocycle or heteroeyele optionally substituted with alkyl, a carbocycle or a heteroeyele; wherein any alkyl, carbocycle or heteroeyele is optionally substituted with halogen, amino, hydroxyl, mcrcapto, carboxyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, alkylthio, acyloxy, acyloxyalkoxy, alkylsulfonyl, 57 Received at IPONZ on 27 February 2012 alkylsulfonylalkyl, alkylsulfinyl, and alkylsulfinylalkyl; and wherein one or more C'I I; or CH groups of any foregoing alkyl is optionally replaced with -0-, -S-, -S(O)-, S(0)2, -N(Rg)-, -C(O)-, -C(0)-NRg-, -NRg-C(O)-, -S02-NR8-, -NR8-S02-, -NR8-C(0)-NR8-, -NRg-C(NH)-NRg-, -NRg-C(NTT)-, -C(0)-0- or -O-C(O)-; 4, The compound of any one of claims 1 to 3, wherein Q is a carbocycle or heteroeyele selected from the group consisting of Ilia - Ills: -(R 7)n Ilia R R? Illb IIIc irid '(R?)n Hie ■w Illf (R/Jn lift "PfJn lilt ^ -A (R?)n IHj (R?)ri 't? Illk III/ Him 58 Received at IPONZ on 2 March 2012 ipiR")n .,N. i ( \ \\ -vf y> v X(^7)n (K?)n VN Illn irio r?' ,-i ~(R7), T .❖N ^ .-N K 'I he coinpciiitw o! anv one of claims I to 4. wherein Xi and X> arc boili O. A irorniKnciJ of claim ecicd iroir. A u ..N-.

A- -N N '•:* u .^-N N"\ ,0.. ,o. o ,nv-nAvV : H O >, Vi ri r, n7 /A / V xx> o f HN'A r\ 59 Received at IPONZ on 2 March 2012 o N H o N -U, o M / /"'N (>. ,0. N' ,N- 0 "N n-• > N- V- NOv N-../ \J H ■k 9 10 N- 6 /-[sj V-NH H .

KL ,.

ISL A, i,,o o a -Nx >•.. N r ,,N. r\ M^/ 0 50 Received at IPONZ on 27 February 2012 Received at IPONZ on 27 February 2012

7. Use of a compound of any one of claims 1 to 6 in the manufacture of a medicament for the treatment of the human or animal body.

8. Use of a compound of any one of claims 1 to 6 in the manufacture of a medicament for the treatment of a disease or condition associated with the overexpression of an IAP in a mammal.

9. Use of a compound of any one of claims 1 to 6 in the manufacture of a medicament for the treatment of cancer.

10. A compound of any one of claims 1 to 6 for use in a method of treatment of the human or animal body.

11. A compound of any one of claims 1 to 6 for use in a method of treatment of a disease or condition associated with the overexpression of an IAP in a mammal.

12. A compound of any one of claims 1 to 6 for use in a method of treatment of cancer.

13. Use of a compound of any one of claims 1 to 6 in combination with a compound selected from the group consisting of cytarabine, fludarabine, 5-fluoro-2'-deoxyuiridinc, genieitabinc. methotrexate, bleomycin, cisplatin, cyclophosphamide, adriamycin (doxorubicin), mitoxantronc, camptothccin, topotccan, colccmid, colchicinc, paclitaxcL vinblastine, vincristine, tamoxifen, finasteride, taxotere and mitomycin C or radiation in the manufacture of a medicament for the treatment of cancer.

14. Use of claim 9 wherein the medicament further comprises a compound selected from the group consisting of cytarabine, fludarabine, 5-ftuoro-2'-deoxyuiridine, gemcitabine, methotrexate, bleomycin, cisplatin, cyclophosphamide, adriamycin (doxorubicin), mitoxantronc, camptothccin, topotccan, colccmid, colchicinc, paclitaxcL vinblastine, vincristine, tamoxifen, finasteride, taxotere and mitomycin C. 62 Received at IPONZ on 2 March 2012

15. Use of claim 9 wherein the medicament is formulated for sequential or concomitant administration with radiation or a compound selected from the group consisting of cytarabine, fludarabine, .vftuoro-S'-deoxyuiridine, gemcitabine, methotrexate, bleomycin, cisplatin, cyclophosphamide, adriamycin (doxorubicin), mitoxantronc, camptothecin, topotecan, eolcemid, colchicine, paclitaxel, vinblastine, vincristine, tamoxifen, finasteride, taxotere and mitomycin C.

16. Use of claim 9 wherein the medicament when administered is administered sequentially or concomitantly with radiation or a compound selected from the group consisting of cytarabine, fludarabine, 5-flu©ra-2*-deoxyuiridhie, gemcitabine, methotrexate, bleomycin, cisplatin, cyclophosphamide, adriamycin (doxorubicin), mitoxantrone, camptothecin, topotecan, cube mid, colchicine, paclitaxel, vinblastine, vincristine, tamoxifen, finasteride, taxotere and mitomycin C.

17. Use of claim 9 wherein the cancer is in a mammal which is also undergoing radiation therapy or chemotherapy.

18. A compound of any one of claims 1 to 6 in combination with a compound selected from the group consisting of cytarabine, fludarabine, 5-fluoro-2'-deoxyuiridine, gemcitabine, methotrexate, bleomycin, cisplatin, cyclophosphamide, adriamycin (doxorubicin), mitoxantrone, camptothecin, topotecan, coicemid. colchicine, paclitaxel, vinblastine, vincristine, tamoxifen, finasteride, taxotere and mitomycin C, or radiation for use in the treatment of cancer. If.

A pharmaceutical composition comprising a compound of any one of claims 1 to 6, and a carrier, diluent or excipient

20. A compound of formula (1) as claimed in any one of claims 1 to 6,10 to 12 and 18, substantially as herein described with reference to any example thereof.

21. A use as claimed in any one of claims 7 to 9 and 13 to 1?, substantially as herein described with reference to any example thereof.

22. A pharmaceutical composition as claimed in claim 19, substantially as herein described with reference to any example thereof. 63 12767697J do 9604164 4 Sequence Listing <110> GENENTECH, INC. et al. <120> IMIDAZOPYRIDINE INHIBITORS OF IAP <130> P2443R1 WO <150> US 60/870,821 <151> 2006-12-19 <160> 1 <210> 1 <211> 133 <212> PRT <213> Homo sapiens <400> 1 Met Gly Ser Ser His His His His His His Ser Ser Gly Leu Val 15 10 15 Pro Arg Gly Ser His Met Leu Glu Thr Glu Glu Glu Glu Glu Glu 20 25 30 Gly Ala Gly Ala Thr Leu Ser Arg Gly Pro Ala Phe Pro Gly Met 35 40 45 Gly Ser Glu Glu Leu Arg Leu Ala Ser Phe Tyr Asp Trp Pro Leu 50 55 60 Thr Ala Glu Val Pro Pro Glu Leu Leu Ala Ala Ala Gly Phe Phe 65 70 75 His Thr Gly His Gin Asp Lys Val Arg Cys Phe Phe Cys Tyr Gly 80 85 90 Gly Leu Gin Ser Trp Lys Arg Gly Asp Asp Pro Trp Thr Glu His 95 100 105 Ala Lys Trp Phe Pro Gly Cys Gin Phe Leu Leu Arg Ser Lys Gly 110 115 120 Gin Glu Tyr lie Asn Asn lie His Leu Thr His Ser Leu 125 130 Page 1 </div>